Preface

Chapter 6 **A5 and A6 Noradrenergic Cell Groups: Implications for**

Manuel Víctor López-González, Marta González-García and Marc

**Cardiorespiratory Control 113**

Stefan Dawid-Milner

**VI** Contents

The autonomic nervous system comprises one of the most important involuntary control mechanisms modulating the function of the visceral organs.

This book consists of six chapters. The introductory chapter provides a general description of the autonomic nervous system, and the extent to which it is addressed, for example, in medical faculties.

The ensuing chapters review and analyze in detail some of the specifics and the role of the autonomic nervous system in the control of vital functions. Particularly interesting is the re‐ view article by López-González, González-García, and Dawid-Milner, titled "A5 and A6 Noradrenergic Cell Groups: Implications for Cardiorespiratory Control," regarding nora‐ drenergic cell groups at the level of the spinal cord controlling the cardiorespiratory system. These projections play a key role in the modulation of all antinociceptive and autonomic responses elicited by painful or threatening situations. The A6 noradrenergic cell group may have the most significant effect on somatosensory transmission, and the A5 group on sym‐ pathetic function.

The shape of dendrites influences the propagation and integration of postsynaptic potentials and determines presynaptic convergence. Dendritc shape is correlated with tonic activity, while aberrant dendritic morphology is associated with disease. There is, therefore, signifi‐ cant interest in understanding how dendritic morphology is regulated in these neurons. In the review article by Chandrasekaran and Lein, titled "Regulation of Dendritogenesis in Sympathetic Neurons," the role of target-derived nerve growth factor in regulating the size of the dendritic arbor of sympathetic neurons *in vivo* is described. In addition, the authors present their own *in vitro* experimental results, which suggest that there are other factors, such as bone morphogenetic proteins, that trigger cultured sympathetic neurons to extend a dendritic arbor comparable with their *in vivo* counterparts.

Clinical practice may benefit from the article by Kingma, Simard, and Rouleau, titled "Auto‐ nomic Nervous System and Neurocardiac Physiopathology," in which the effect of auto‐ nomic neural dysfunction in arrhythmogenesis is analyzed in detail. Disorders within the autonomic nervous system contribute to pathogenesis of organ injury, comorbidities, and may even impact survival. Improved comprehension of modifications within the cardiac/ neuro axis at the molecular, cellular, organ, and whole-body levels is critical for the develop‐ ment of therapeutic strategies.

The review article by Proshchina et al., titled **"**Development of Human Pancreatic Innerva‐ tion,**"** addresses human pancreatic innervation, which is of particular interest due to its pos‐ sible role in the pathogenesis of such diseases as diabetes mellitus, pancreatitis, and

pancreatic cancer. It has been suggested that pancreatic autonomic innervation plays an im‐ portant role, not only in the regulation of endocrine and exocrine activity, but also in normal islet morphogenesis.

The association between inflammation and common human diseases remains an unsolved mystery in contemporary biology and medicine. Inflammation, as a response to infection, impacts different parts of the nervous system. In fact, recent studies have indicated that sys‐ temic inflammation can be attenuated by autonomic nerve fibers. The article by Leal et al., titled "Inflammation and the Autonomic Function," analyzes the general autonomic mecha‐ nisms controlling inflammatory responses in several conditions, including burn processes, rheumatoid arthritis, and obesity, with a special focus on the inflammatory processes associ‐ ated with sepsis.

This book may stimulate interest in many researchers who could use this information to ad‐ vance their research towards a better understanding of autonomic regulatory mechanisms.

**Pavol Svorc, Assoc. Prof., Dr., Ph.D.**

Department of Physiology Faculty of Medicine Safarik's University Košice, Slovak Republic **Section 1**

**Autonomic Nervous System**

**Autonomic Nervous System**

pancreatic cancer. It has been suggested that pancreatic autonomic innervation plays an im‐ portant role, not only in the regulation of endocrine and exocrine activity, but also in normal

The association between inflammation and common human diseases remains an unsolved mystery in contemporary biology and medicine. Inflammation, as a response to infection, impacts different parts of the nervous system. In fact, recent studies have indicated that sys‐ temic inflammation can be attenuated by autonomic nerve fibers. The article by Leal et al., titled "Inflammation and the Autonomic Function," analyzes the general autonomic mecha‐ nisms controlling inflammatory responses in several conditions, including burn processes, rheumatoid arthritis, and obesity, with a special focus on the inflammatory processes associ‐

This book may stimulate interest in many researchers who could use this information to ad‐ vance their research towards a better understanding of autonomic regulatory mechanisms.

**Pavol Svorc, Assoc. Prof., Dr., Ph.D.**

Department of Physiology Faculty of Medicine Safarik's University Košice, Slovak Republic

islet morphogenesis.

VIII Preface

ated with sepsis.

**Chapter 1**

Provisional chapter

**Introductory Chapter: Autonomic Nervous System -**

DOI: 10.5772/intechopen.81026

The nervous system captures and processes stimuli acting on an organism and provides the means for an adequate response. It provides neural control that is faster than hormonal pathways and is, therefore, more suitable for transmitting information that requires a rapid, coordinated response. The sensory, somatic, and autonomic parts of the nervous system have been extensively studied. What is the physiology of the autonomic nervous system and what

The autonomic (vegetative) nervous system is an involuntary system that primarily controls and modulates the functions of the visceral organs. Similarly, through the control of somatic functions, a relatively large part of autonomic regulation is controlled through the reflex arc. The autonomic nervous system innervates the smooth muscles of vessels, digestive system, bladder and urethra, lower airways, cardiac muscle, sweat and lacrimal glands, and adrenal medulla. The autonomic nervous system has three branches: sympathetic, parasympathetic, and enteric [1–4]. In many cases, the sympathetic and parasympathetic nervous systems have "opposite" actions, in which one system activates and the other inhibits a physiological response. The current view is that the sympathetic nervous system is a "quick response mobilizing system" and the parasympathetic nervous system is a "more slowly activated

The enteric—or intrinsic—nervous system is one of the main divisions of the autonomic nervous system and consists of a network of neurons that manage the functions of the gastrointestinal tract [5]. It is capable of acting independently of the sympathetic and parasympathetic nervous systems; however, it may be modulated by sympathetic and parasympathetic activity. The main components are the plexus myentericus (Auerbach), which mainly influences motility, and the plexus submucosus (Meissner), which is responsible for glandular secretions [6]. The enteric nervous system has also been referred to as the "second brain" [7].

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Introductory Chapter: Autonomic Nervous System -

**What We Know About It**

What We Know About It

http://dx.doi.org/10.5772/intechopen.81026

Additional information is available at the end of the chapter

do we teach students about this system in medical faculties?

Additional information is available at the end of the chapter

Pavol Svorc

Pavol Svorc

1. Introduction

inhibitory system."

#### **Introductory Chapter: Autonomic Nervous System - What We Know About It** Introductory Chapter: Autonomic Nervous System - What We Know About It

DOI: 10.5772/intechopen.81026

#### Pavol Svorc Pavol Svorc

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.81026

#### 1. Introduction

The nervous system captures and processes stimuli acting on an organism and provides the means for an adequate response. It provides neural control that is faster than hormonal pathways and is, therefore, more suitable for transmitting information that requires a rapid, coordinated response. The sensory, somatic, and autonomic parts of the nervous system have been extensively studied. What is the physiology of the autonomic nervous system and what do we teach students about this system in medical faculties?

The autonomic (vegetative) nervous system is an involuntary system that primarily controls and modulates the functions of the visceral organs. Similarly, through the control of somatic functions, a relatively large part of autonomic regulation is controlled through the reflex arc. The autonomic nervous system innervates the smooth muscles of vessels, digestive system, bladder and urethra, lower airways, cardiac muscle, sweat and lacrimal glands, and adrenal medulla. The autonomic nervous system has three branches: sympathetic, parasympathetic, and enteric [1–4]. In many cases, the sympathetic and parasympathetic nervous systems have "opposite" actions, in which one system activates and the other inhibits a physiological response. The current view is that the sympathetic nervous system is a "quick response mobilizing system" and the parasympathetic nervous system is a "more slowly activated inhibitory system."

The enteric—or intrinsic—nervous system is one of the main divisions of the autonomic nervous system and consists of a network of neurons that manage the functions of the gastrointestinal tract [5]. It is capable of acting independently of the sympathetic and parasympathetic nervous systems; however, it may be modulated by sympathetic and parasympathetic activity. The main components are the plexus myentericus (Auerbach), which mainly influences motility, and the plexus submucosus (Meissner), which is responsible for glandular secretions [6]. The enteric nervous system has also been referred to as the "second brain" [7].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## 2. Composition

The composition of the efferent pathway is the same for both the sympathetic and parasympathetic divisions. It consists of two types of neurons:

4. Sympathetic division

periarteriorlarly.

From an anatomical perspective, the sympathetic division represents the thoracolumbal component of the autonomic nervous system. This system is the primary mechanism that controls the "fight-or-flight" response. The sympathetic part is dominant in stressful situations, espe-

Introductory Chapter: Autonomic Nervous System - What We Know About It

http://dx.doi.org/10.5772/intechopen.81026

5

Axons of neurons C8–L3 (nucleus [ncl.] intermedial and ncl. intermediolateralis) leave the spinal cord by the ventral roots of the rami communicantes albi and enter the sympathetic trunk. In this part, most neural connetions are placed. Only a part of the neuron is interconnected in the prevertebral ganglia. Ganglionic fibers proceed to the organs either through the rami viscerales (from the sympathetic trunk) or through the rami communicantes grisey and further by sensory neurons to the periphery (especially the skin). Fibers from the rami viscerales proceed most often

cially when an organism prepares for situations associated with high-energy output.

5. Neurotransmitters and receptors of the autonomic nervous system

depolarization-excitatory effect on ganglionic neurons.

of bronchial smooth muscle induces bronchodilatation.

nomic function, particularly in the gut and lungs [8].

6. Mechanism of action

Acetylcholine binds to two types of membrane receptor: muscarinic and nicotinic. Muscarinic receptors are located on the membranes of effector cells, between the terminals of the postganglionic parasympathetic and sympathetic cholinergic fibers and effector organs. Their activation exhibits a slower excitatory effect. Nicotinic receptors are localized to the membranes of ganglionic parasympathetic and sympathetic neurons, and their activation exhibits a rapid

Noradrenaline is a neurotransmitter of the sympathetic part of the autonomic nervous system. It binds to two types of membrane receptors: α-adrenergic and β-adrenergic. The results of the combinations are different responses of the effector organs. For example, stimulation of αreceptors on vessel smooth muscle induces vasoconstriction, while stimulation of β-receptors

There are inhibitory and excitatory synapses between neurons. Relatively recently, the third subsystem of neurons, known as non-adrenergic, non-cholinergic transmitters (because they use nitric oxide as a neurotransmitter), has been described and found to be integral to auto-

α1-Receptors are found in the vascular smooth muscle of the skin and splanchnic region, in the

sphincters of the gastrointestinal tract and bladder, and in the radial muscle of the iris:


### 3. Parasympathetic division

From an anatomical perspective, the parasympathetic division is the craniosacral component of the autonomic nervous system. This system is the primary mechanism that controls "rest and digest." The parasympathetic part is dominant in rest conditions, especially when an organism progresses from states of energetic exacting stress to a rest state.


### 4. Sympathetic division

2. Composition

4 Autonomic Nervous System

neurons.

Cranial part Ncl. Edinger-Westphal

Ncl. salivatorius superior

Ncl. salivatorius inferior

Ncl. dorsalis n. vagi

Sacral part Ncl.

intermediolateralis

lionic neurons.

3. Parasympathetic division

thetic divisions. It consists of two types of neurons:

The composition of the efferent pathway is the same for both the sympathetic and parasympa-

• The first type is located in the brain stem or spinal cord and is referred to as preganglionic

• The second type is located in the ganglia, or in the body itself, and is referred to as postgang-

From an anatomical perspective, the parasympathetic division is the craniosacral component of the autonomic nervous system. This system is the primary mechanism that controls "rest and digest." The parasympathetic part is dominant in rest conditions, especially when an

Ggl. pterygopalatinum Nn.

Ggl. oticum N.

the heart and in the respiratory and digestive systems

Ggl. ciliare Nn. ciliares breves M. sphincter

pterygopalatini N. zygomaticus N. lacrimalis

Ggl. submandibulare Nn. lingualis Submandibular and

auriculotemporalis

N. vagi (X. cranial

nerve)

Plexus hypogastricus inferior

pupillae (miosis) and M. ciliaris (accommodation)

sublingual salivary

Parotid gland

Tear gland

glands

organism progresses from states of energetic exacting stress to a rest state.

N. vagi (X. cranial nerve) Intramural ganglia in

N. oculomotorius (III. cranial nerve) and its ramus inferior

N. facialis (VII. cranial nerve) and branch of n. petrosus

N. facialis (VII. cranial nerve), chorda tympani, and n.

N. glossopharyngeus (IX. cranial nerve) and branches of n. petrosus minor and n.

major

lingualis

tympanicus

Output Preganglionic Ganglion Postganglionic Effector

From an anatomical perspective, the sympathetic division represents the thoracolumbal component of the autonomic nervous system. This system is the primary mechanism that controls the "fight-or-flight" response. The sympathetic part is dominant in stressful situations, especially when an organism prepares for situations associated with high-energy output.

Axons of neurons C8–L3 (nucleus [ncl.] intermedial and ncl. intermediolateralis) leave the spinal cord by the ventral roots of the rami communicantes albi and enter the sympathetic trunk. In this part, most neural connetions are placed. Only a part of the neuron is interconnected in the prevertebral ganglia. Ganglionic fibers proceed to the organs either through the rami viscerales (from the sympathetic trunk) or through the rami communicantes grisey and further by sensory neurons to the periphery (especially the skin). Fibers from the rami viscerales proceed most often periarteriorlarly.

#### 5. Neurotransmitters and receptors of the autonomic nervous system

Acetylcholine binds to two types of membrane receptor: muscarinic and nicotinic. Muscarinic receptors are located on the membranes of effector cells, between the terminals of the postganglionic parasympathetic and sympathetic cholinergic fibers and effector organs. Their activation exhibits a slower excitatory effect. Nicotinic receptors are localized to the membranes of ganglionic parasympathetic and sympathetic neurons, and their activation exhibits a rapid depolarization-excitatory effect on ganglionic neurons.

Noradrenaline is a neurotransmitter of the sympathetic part of the autonomic nervous system. It binds to two types of membrane receptors: α-adrenergic and β-adrenergic. The results of the combinations are different responses of the effector organs. For example, stimulation of αreceptors on vessel smooth muscle induces vasoconstriction, while stimulation of β-receptors of bronchial smooth muscle induces bronchodilatation.

There are inhibitory and excitatory synapses between neurons. Relatively recently, the third subsystem of neurons, known as non-adrenergic, non-cholinergic transmitters (because they use nitric oxide as a neurotransmitter), has been described and found to be integral to autonomic function, particularly in the gut and lungs [8].

#### 6. Mechanism of action

α1-Receptors are found in the vascular smooth muscle of the skin and splanchnic region, in the sphincters of the gastrointestinal tract and bladder, and in the radial muscle of the iris:

1. The α1-receptor is embedded in the cell membrane, where it is coupled via a Gq protein to phospholipase C. In the inactive state, the α<sup>q</sup> subunit of the heterotrimeric Gq protein is bound to GDP.

4. Activated adenylyl cyclase catalyzes the conversion of ATP to cAMP, which serves as the second messenger. cAMP, via the steps involving activation of protein kinases, initiates the

Introductory Chapter: Autonomic Nervous System - What We Know About It

http://dx.doi.org/10.5772/intechopen.81026

Nicotinic receptors are found in several important locations: on the motor end plate of skeletal muscle, on all postganglionic neurons of both the sympathetic and parasympathetic nervous

five subunits: two α, one β, one δ, and one γ. These five subunits form a funnel around the

2. When acetylcholine is bound to each of the two α-subunits, a conformational change occurs in all of the subunits, resulting in opening of the central core of the channel. When the core of the channel opens, Na+ and K+ flow down their respective electrochemical

Muscarinic receptors are located in all of the effector organs of the parasympathetic nervous system: in the heart, gastrointestinal tract, bronchioles, bladder, and male sex organs. These receptors also are found in certain effector organs of the sympathetic nervous system, specifi-

1. Some muscarinic receptors have the same mechanism of action as α1-adrenoreceptors. In these cases, binding of acetylcholine to the muscarinic receptor causes dissociation of the αsubunit of the G protein, activation of phospholipase C, and production of IP3 and diacylglycerol. IP3 releases stored Ca2+, and increased intracellular Ca2+ with diacylglycerol

2. Other muscarinic receptors alter physiological processes via direct action of the G protein. In these cases, no other second messenger is involved. For example, muscarinic receptors in the cardiac sinoatrial node, when activated by Ach, produce activation of a Gi-protein and release of the αI-subunit, which binds directly to the K+ channel of the sinoatrial node. When the αI-subunit binds to K+ channels, the channels open, slowing the rate of depolar-

Centers of the autonomic nervous system are regarded to be integrators of responses to internal and external stimuli that are related to the control of autonomic functions. From this perspective, there are probably no autonomic centers in the spinal cord, although all sympathetic and sacral parasympathetic fibers extend outward from the spinal cord. It is not clear whether there are centers controlling and coordinating the activities of the relevant parts of the autonomic nervous system or whether they are only peripheral centers. Similarly, the importance of the brain cortex, which is involved in the control of autonomic functions, lies in the integration and generation of conditioned reflexes associated with the autonomic nerves.

mouth of a central core. When no acetylcholine is bound, the channel is closed.

. The receptor has

7

final physiological actions.

gradients.

cally, in sweat glands:

systems, and on the chromaffin cells of the adrenal medulla:

produces tissue-specific physiological actions.

ization of the sinoatrial node, and decreasing heart rate.

7. Autonomic nervous system: autonomic centers

1. The nicotinic receptor for acetylcholine is an ion channel for Na+ and K<sup>+</sup>


α2-Receptors are less common than α1-receptors; they are found in the walls of the gastrointestinal tract and in presynaptic adrenergic nerve terminals:


β1-Receptors are prominent in the heart (increase in activity), in the saliva glands (increase in secretion), in the adipose tissue, and in the kidney (where they promote renin secretion).

β2-Receptors are found in the vascular smooth muscle of skeletal muscle, in the walls of the gastrointestinal tract and bladder, and in the bronchioles. The activation of β2-receptors in these tissue leads to relaxation or dilatation:


4. Activated adenylyl cyclase catalyzes the conversion of ATP to cAMP, which serves as the second messenger. cAMP, via the steps involving activation of protein kinases, initiates the final physiological actions.

1. The α1-receptor is embedded in the cell membrane, where it is coupled via a Gq protein to phospholipase C. In the inactive state, the α<sup>q</sup> subunit of the heterotrimeric Gq protein is

2. When an agonist, such as noradrenaline, binds to the α1-receptor, a conformational change occurs in the α<sup>q</sup> subunit of the Gq protein that has two effects: GDP is released from the α<sup>q</sup> subunit and replaced by GTP, and the α<sup>q</sup> subunit (with GTP attached) detaches from the

3. The αq-GTP complex migrates within the cell membrane and binds to and activates phospholipase C. Intrinsic GTPase activity then converts GTP back to GDP, and the α<sup>q</sup>

4. Activated phospholipase C catalyzes the liberation of diacylglycerol and IP3 from phosphatidylinositol 4,5-diphosphate. The IP3 that is generated causes the release of Ca2+ from intracellular stores in the endoplasmic or sarcoplasmic reticulum, resulting in an increase in intracellular Ca2+ concentration. Together, Ca2+ and diacylglycerol activate protein kinase C, which in turn phosphorylates proteins. These phosphorylated proteins execute the final

α2-Receptors are less common than α1-receptors; they are found in the walls of the gastrointes-

1. The agonist (noradrenaline) binds to the α<sup>2</sup>receptor, which is coupled to adenyl cyclase

2. When noradrenaline is bound, Gi protein releases GDP and binds to GTP, and the α<sup>i</sup>

3. The αi-subunit then migrates in the membrane and binds to and inhibits adenyl cyclase. As a result, cAMP levels decrease, producing the final physiological action. For example,

β1-Receptors are prominent in the heart (increase in activity), in the saliva glands (increase in secretion), in the adipose tissue, and in the kidney (where they promote renin secretion).

β2-Receptors are found in the vascular smooth muscle of skeletal muscle, in the walls of the gastrointestinal tract and bladder, and in the bronchioles. The activation of β2-receptors in

1. β2-Receptors are embedded in the cell membrane. They are coupled, via a GS protein, to adenylyl cyclase. In the inactive state, the αS-subunit of the GS-protein is bound to GDP. 2. When an agonist, such as noradrenaline, binds to the β2-receptor, a conformational change occurs in the αS-subunit. This change has two effects: GDP is released from the αS-subunit and replaced by GTP, and the activated αS-subunit detaches from the G protein complex.

3. The αS-GTP complex migrates within the cell membrane and binds to and activates adenylyl cyclase. GTPase activity converts GTP back to GDP, and the α<sup>S</sup> subunit is

activation of α2-receptors in the wall of the gastrointestinal tract causes relaxation.

bound to GDP.

6 Autonomic Nervous System

rest of the Gq protein.

subunit returns to the inactive state (not shown).

tinal tract and in presynaptic adrenergic nerve terminals:

subunit dissociates from the G protein complex.

by an inhibitory G protein (Gi).

these tissue leads to relaxation or dilatation:

returned to its inactive state.

physiological actions, such as contraction of smooth muscle.

Nicotinic receptors are found in several important locations: on the motor end plate of skeletal muscle, on all postganglionic neurons of both the sympathetic and parasympathetic nervous systems, and on the chromaffin cells of the adrenal medulla:


Muscarinic receptors are located in all of the effector organs of the parasympathetic nervous system: in the heart, gastrointestinal tract, bronchioles, bladder, and male sex organs. These receptors also are found in certain effector organs of the sympathetic nervous system, specifically, in sweat glands:


#### 7. Autonomic nervous system: autonomic centers

Centers of the autonomic nervous system are regarded to be integrators of responses to internal and external stimuli that are related to the control of autonomic functions. From this perspective, there are probably no autonomic centers in the spinal cord, although all sympathetic and sacral parasympathetic fibers extend outward from the spinal cord. It is not clear whether there are centers controlling and coordinating the activities of the relevant parts of the autonomic nervous system or whether they are only peripheral centers. Similarly, the importance of the brain cortex, which is involved in the control of autonomic functions, lies in the integration and generation of conditioned reflexes associated with the autonomic nerves.

Regarding the brainstem and hypothalamus. Reticular formation is responsible for the regulation of the cardiovascular and respiratory systems and is the center of some autonomic reflexes. The cardiovascular center includes the following structures:

there are projections into the lateral part of the hypothalamus: ncl. paraventricularis and ncl. dorsomedialis. All of these structures contain two types of neurons: orexigenic, which synthesize substances, of which higher levels correlate with increased ingestion of food and activate the ncl. ventromedialis, and anorexigenic, which synthesize substances, of which higher levels

Introductory Chapter: Autonomic Nervous System - What We Know About It

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9

Thirst is the body's response to a lack of fluids, and there are two types of dehydration. The first type is the shortage of water (mostly in well-trained athletes, who secrete thin "water" sweat). In this case, the blood is concentrated, but only briefly, because water from the intercellular spaces immediately starts to flow into the blood, resulting in increases in salt concentration in the extracellular fluid. In response, water from cells moves into the intercellular spaces and, thus, results in partial dehydration. The second type of dehydration is not only the loss of water but also a large amount of salts (untrained athletes secrete dense "salty" sweat), which are mainly in the blood and in the extracellular fluids. This usually results in only a slight increase in the concentration of ions (salts) in the extracellular fluid. In this type of dehydration, water content in the cells remains stable; however, the amount of circulating blood and intercellular fluid is

The ncl. paraventricularis contains cells that are in the contact with blood flow and cerebrospinal fluid and respond either by initiating thirst or, conversely, by initiating the urge to urinate. Stimuli are from osmoreceptors (on cue from increases in osmotically active substances in the extracellular fluid), from the renin-angiotensin system (decreased plasma volume; greater concentrations of angiotensin II elevate blood pressure and cause the feeling of thirst) and baroreceptors (decrease in plasma volume). If there is a fluid deficiency in the body, the

The preoptic area in the hypothalamus is responsible for monitoring body temperature and for reactions to increases in temperature. Extreme increases in temperature are apparent when this area is injured or damaged. The area hypothalamica posterior contains neurons that do not directly monitor body temperature; however, they react to the information from peripheral and central thermoreceptors and activate output functions of thermoregulation. Output functions of thermoregulation are concentrated on the maintenance of adequate body temperature

Control through the hypothalamic-hypophyseal tract (ncl. paraventricularis and ncl. supraopticus—antidiuretic hormone and oxytocin) and hypothalamic sympathetic fibers influences adrenaline and noradrenaline secretion. The hypothalamus also controls the secretory activity of the anterior pituitary gland through the release of liberins and inhibitory (inhibins)

pressure in the veins is small, and blood becomes too "dense."

and protection of the organism against hypothermia.

8.4. Control of body temperature

8.5. Control of the endocrine glands

correlate with reduced intake of food.

8.3. Center of thirst

reduced.

factors.


### 8. Hypothalamus

The function of the hypothalamus is highly complex; in fact, there is no important activity in the body that is not regulated in some way by the hypothalamus.

#### 8.1. Center of hunger and satiety

The satiety center is located near the regulatory centers for secretion of hormones and endocrine processes in the body. The center of hunger is located near the center of satiety. Hunger is a feeling (unconditioned reaction of the body) caused by the lack of food. It is an important signal and one that prompts the body about the need for food intake and the energy from it. Hunger occurs when blood glucose levels fall below a certain level. The need for food intake is also influenced by signals from the digestive system and, by the action of certain hormones, state of mind and/or state of attention, among others, may play a role. Feelings of hunger vary among individuals, with different speeds and intensities, and are tolerated differently—some tolerate hunger well, while in others, it is associated with mood changes manifesting as irritability or fractiousness. Prolonged starvation leads to elimination of psychological barriers and principles (e.g., cannibalism from situational emergency), with hallucinations or paranoia.

#### 8.2. Control of food intake

It is assumed that the information from the periphery (sensory inputs from the digestive tract, including gustatory afferentation) is guided into the ncl. arcuatus in the hypothalamus, where there are projections into the lateral part of the hypothalamus: ncl. paraventricularis and ncl. dorsomedialis. All of these structures contain two types of neurons: orexigenic, which synthesize substances, of which higher levels correlate with increased ingestion of food and activate the ncl. ventromedialis, and anorexigenic, which synthesize substances, of which higher levels correlate with reduced intake of food.

#### 8.3. Center of thirst

Regarding the brainstem and hypothalamus. Reticular formation is responsible for the regulation of the cardiovascular and respiratory systems and is the center of some autonomic reflexes.

• The pressoric area is located on both sides of the dorsolateral part of the reticular formation. Increased activity leads to an increase in blood pressure. Sympathetic preganglionic neurons innervating the heart, blood vessels, and juxtaglomerular apparatus are efferent pathways

• The depressoric area is located in the ventromedial part of both sides of the reticular formation. Increased activity leads to decrease in blood pressure and, reciprocally, is

• The respiratory center is functionally situated in the autonomic centers because it affects the spinal motor neurons controlling breathing movements through the autonomic respi-

• The autonomic reflexes are associated with input and processing of food. It is a reflex encompassing sucking, swallowing, salivation, secretion of gastric and pancreatic juices,

The function of the hypothalamus is highly complex; in fact, there is no important activity in

The satiety center is located near the regulatory centers for secretion of hormones and endocrine processes in the body. The center of hunger is located near the center of satiety. Hunger is a feeling (unconditioned reaction of the body) caused by the lack of food. It is an important signal and one that prompts the body about the need for food intake and the energy from it. Hunger occurs when blood glucose levels fall below a certain level. The need for food intake is also influenced by signals from the digestive system and, by the action of certain hormones, state of mind and/or state of attention, among others, may play a role. Feelings of hunger vary among individuals, with different speeds and intensities, and are tolerated differently—some tolerate hunger well, while in others, it is associated with mood changes manifesting as irritability or fractiousness. Prolonged starvation leads to elimination of psychological barriers and principles (e.g., cannibalism from situational emergency), with hallucinations or paranoia.

It is assumed that the information from the periphery (sensory inputs from the digestive tract, including gustatory afferentation) is guided into the ncl. arcuatus in the hypothalamus, where

• The ncl. dorsalis n. vagi is the source of vagal parasympathetic afferentation.

The cardiovascular center includes the following structures:

ratory rhythm generator and inspiration rhythm.

the body that is not regulated in some way by the hypothalamus.

from this center.

8 Autonomic Nervous System

and vomiting.

8. Hypothalamus

8.1. Center of hunger and satiety

8.2. Control of food intake

connected to the pressoric area.

Thirst is the body's response to a lack of fluids, and there are two types of dehydration. The first type is the shortage of water (mostly in well-trained athletes, who secrete thin "water" sweat). In this case, the blood is concentrated, but only briefly, because water from the intercellular spaces immediately starts to flow into the blood, resulting in increases in salt concentration in the extracellular fluid. In response, water from cells moves into the intercellular spaces and, thus, results in partial dehydration. The second type of dehydration is not only the loss of water but also a large amount of salts (untrained athletes secrete dense "salty" sweat), which are mainly in the blood and in the extracellular fluids. This usually results in only a slight increase in the concentration of ions (salts) in the extracellular fluid. In this type of dehydration, water content in the cells remains stable; however, the amount of circulating blood and intercellular fluid is reduced.

The ncl. paraventricularis contains cells that are in the contact with blood flow and cerebrospinal fluid and respond either by initiating thirst or, conversely, by initiating the urge to urinate. Stimuli are from osmoreceptors (on cue from increases in osmotically active substances in the extracellular fluid), from the renin-angiotensin system (decreased plasma volume; greater concentrations of angiotensin II elevate blood pressure and cause the feeling of thirst) and baroreceptors (decrease in plasma volume). If there is a fluid deficiency in the body, the pressure in the veins is small, and blood becomes too "dense."

#### 8.4. Control of body temperature

The preoptic area in the hypothalamus is responsible for monitoring body temperature and for reactions to increases in temperature. Extreme increases in temperature are apparent when this area is injured or damaged. The area hypothalamica posterior contains neurons that do not directly monitor body temperature; however, they react to the information from peripheral and central thermoreceptors and activate output functions of thermoregulation. Output functions of thermoregulation are concentrated on the maintenance of adequate body temperature and protection of the organism against hypothermia.

#### 8.5. Control of the endocrine glands

Control through the hypothalamic-hypophyseal tract (ncl. paraventricularis and ncl. supraopticus—antidiuretic hormone and oxytocin) and hypothalamic sympathetic fibers influences adrenaline and noradrenaline secretion. The hypothalamus also controls the secretory activity of the anterior pituitary gland through the release of liberins and inhibitory (inhibins) factors.

#### 8.6. Relationship with sexual function

The hypothalamus has an association with all sexual activities including sexual development, the menstrual cycle, ovulation, erection, copulation, ejaculation, pregnancy, birth, lactation, and sexual urges and behavior. Injury to the anterior hypothalamus results in disordered libido, while injury to the posterior hypothalamus results in increased sexual urges.

such as hypertension, type 2 diabetes mellitus, and/or gastric ulceration. Hypothalamic disorders can cause damage to thermoregulation, circadian rhythms, insomnia, the menstrual cycle, premature maturation, growth disturbances, eating disorders (aphagia and subsequent anorexia, hyperphagia may develop), or hormone production disorders [6].

Introductory Chapter: Autonomic Nervous System - What We Know About It

http://dx.doi.org/10.5772/intechopen.81026

11

Therefore, proper and early diagnosis of autonomic nervous system disorders forms the basis of successful treatment. Symptoms that indicate autonomic system disorders include sweating, digestive disorders, dizziness, changes in heart rate, or urinary problems. Objectively, the autonomic nervous system can be investigated using classical and special methods. Classical methods include, in particular, the examination of cardiovascular reflexes, Valsalva maneuver, orthostatic test, or deep breathing. These tests do not, however, evaluate the extent of dysfunction [9]. Currently, a special method for examining autonomic nervous system activity involves the measurement of heart rate variability. This is a parameter that reflects the current functional state of the autonomic nervous system. In recent years, heart rate variability measurement has also attracted attention outside of research in everyday clinical and outpatient practice and in health promotion [10]. Parameters of heart rate variability are able to provide information about the proportion of sympathetic and parasympathetic components with respect to respiration or thermoregulation. Heart rate is also affected by many other factors that can increase sympathetic tone, for example, male sex, younger age, and violent emotions. Female sex, older age, or good physical condition may be involved in reducing heart rate. Heart rate variability determination is performed

From this perspective, detailed study of the functions and mechanisms of the autonomic

Department of Physiology, Faculty of Medicine, Safarik University, Kosice, Slovak Republic

[1] Langley JN. The Autonomic Nervous System. Part 1. Cambridge: W. Heffer; 1921

edia.4064. Archived from the Original on 8 October 2017

[2] Jänig W. Integrative Action of the Autonomic Nervous System: Neurobiology of Homeostasis (Digitally Printed Version. ed.). Cambridge: Cambridge University Press; 2008. p.13.

[3] Furness J. Enteric nervous system. Scholarpedia. 2007;2(10):4064. DOI: 10.4249/scholarp-

using time or spectral analysis methods.

nervous system is important and necessary.

Address all correspondence to: pavol.svorc@upjs.sk

Author details

Pavol Svorc

References

ISBN: 978052106754-6

#### 8.7. Control of emotions

Emotions are psychological processes that involve subjective experiences of comfort and discomfort linked to physiological changes (changes in heart rate and respiratory rate), motor manifestations (mimics, gesticulation), change readiness, and concentration. Emotions induce and influence other psychological processes. Hypothalamic nuclei, together with the anterior nuclei of the thalamus and cingulate gyrus, form the Papez circuit, which is an important part of the limbic system. They represent a very close structural relationship and, thus, represent the basis for the formation of autonomic manifestations of emotion.

#### 8.8. Control of biological rhythms

Rhythmic activity is generated by the ncl. suprachiasmaticus. Rhythmic hypothalamic processes extend into practically all other functions of the hypothalamus as sympathetic tone, hormone secretion, regulation of temperature, intake of food and fluids, sexual function, emotion, and immune processes.

Other relationships include relation to sleep (sleep center in the anterior hypothalamus and center of wakefulness in the posterior hypothalamus), immunity (mediated by changes in the production of hormones [glucocorticoid production]), and changes in the tone of the autonomic nervous system. Sympathetic-immune interactions particularly affect the secondary lymphoid organs (spleen, lymph nodes) and are believed to increase preparedness for escape/ attack. Relation to memory (Papez's circuit—transmission of short-term to long-term memory), complex behavior (motivations, emotions), control of metabolism (through control of the endocrine glands—secretion of adrenaline, adrenocorticotropic hormone, etc.), sensory function and relation to the motor system ninvoluntary movements, extrapyramidal tract, basal ganglia).

#### 9. Clinical practice

Disorders of the autonomic nervous system result in relatively serious neurological conditions. For example, excessive activation of the sympathetic nervous system by emotions, painful stimuli, and drops in blood pressure, such as hemorrhagic shock or hypoglycemia, trigger a prepared stress response from the body. Chronically increased sympathetic activity (sleep deprivation and social insecurity, among others) can lead to psychosomatic disorders such as hypertension, type 2 diabetes mellitus, and/or gastric ulceration. Hypothalamic disorders can cause damage to thermoregulation, circadian rhythms, insomnia, the menstrual cycle, premature maturation, growth disturbances, eating disorders (aphagia and subsequent anorexia, hyperphagia may develop), or hormone production disorders [6].

Therefore, proper and early diagnosis of autonomic nervous system disorders forms the basis of successful treatment. Symptoms that indicate autonomic system disorders include sweating, digestive disorders, dizziness, changes in heart rate, or urinary problems. Objectively, the autonomic nervous system can be investigated using classical and special methods. Classical methods include, in particular, the examination of cardiovascular reflexes, Valsalva maneuver, orthostatic test, or deep breathing. These tests do not, however, evaluate the extent of dysfunction [9]. Currently, a special method for examining autonomic nervous system activity involves the measurement of heart rate variability. This is a parameter that reflects the current functional state of the autonomic nervous system. In recent years, heart rate variability measurement has also attracted attention outside of research in everyday clinical and outpatient practice and in health promotion [10]. Parameters of heart rate variability are able to provide information about the proportion of sympathetic and parasympathetic components with respect to respiration or thermoregulation. Heart rate is also affected by many other factors that can increase sympathetic tone, for example, male sex, younger age, and violent emotions. Female sex, older age, or good physical condition may be involved in reducing heart rate. Heart rate variability determination is performed using time or spectral analysis methods.

From this perspective, detailed study of the functions and mechanisms of the autonomic nervous system is important and necessary.

### Author details

#### Pavol Svorc

8.6. Relationship with sexual function

urges.

ganglia).

9. Clinical practice

8.7. Control of emotions

10 Autonomic Nervous System

8.8. Control of biological rhythms

emotion, and immune processes.

The hypothalamus has an association with all sexual activities including sexual development, the menstrual cycle, ovulation, erection, copulation, ejaculation, pregnancy, birth, lactation, and sexual urges and behavior. Injury to the anterior hypothalamus results in disordered libido, while injury to the posterior hypothalamus results in increased sexual

Emotions are psychological processes that involve subjective experiences of comfort and discomfort linked to physiological changes (changes in heart rate and respiratory rate), motor manifestations (mimics, gesticulation), change readiness, and concentration. Emotions induce and influence other psychological processes. Hypothalamic nuclei, together with the anterior nuclei of the thalamus and cingulate gyrus, form the Papez circuit, which is an important part of the limbic system. They represent a very close structural relationship and, thus, represent

Rhythmic activity is generated by the ncl. suprachiasmaticus. Rhythmic hypothalamic processes extend into practically all other functions of the hypothalamus as sympathetic tone, hormone secretion, regulation of temperature, intake of food and fluids, sexual function,

Other relationships include relation to sleep (sleep center in the anterior hypothalamus and center of wakefulness in the posterior hypothalamus), immunity (mediated by changes in the production of hormones [glucocorticoid production]), and changes in the tone of the autonomic nervous system. Sympathetic-immune interactions particularly affect the secondary lymphoid organs (spleen, lymph nodes) and are believed to increase preparedness for escape/ attack. Relation to memory (Papez's circuit—transmission of short-term to long-term memory), complex behavior (motivations, emotions), control of metabolism (through control of the endocrine glands—secretion of adrenaline, adrenocorticotropic hormone, etc.), sensory function and relation to the motor system ninvoluntary movements, extrapyramidal tract, basal

Disorders of the autonomic nervous system result in relatively serious neurological conditions. For example, excessive activation of the sympathetic nervous system by emotions, painful stimuli, and drops in blood pressure, such as hemorrhagic shock or hypoglycemia, trigger a prepared stress response from the body. Chronically increased sympathetic activity (sleep deprivation and social insecurity, among others) can lead to psychosomatic disorders

the basis for the formation of autonomic manifestations of emotion.

Address all correspondence to: pavol.svorc@upjs.sk

Department of Physiology, Faculty of Medicine, Safarik University, Kosice, Slovak Republic

#### References


[4] Willis WD. The autonomic nervous system and its central control. In: Berne, RM. Physiology. 5th ed. St. Louis, MO: Mosby; 2004. ISBN 0323022251

**Section 2**

**Autonomic Nervous System and Digestion**


**Autonomic Nervous System and Digestion**

[4] Willis WD. The autonomic nervous system and its central control. In: Berne, RM. Physiol-

[5] Furness JB. The Enteric Nervous System. John Wiley & Sons, e-book; 2008. pp. 35-38. ISBN:

[6] Šlamberová R. Fyziologie a patofyziologie autonomního nervového systému. In: Rokyta R et al., editors. Fyziologie a Patologická Fyziologie pro Klinickou Praxi. Praha: Grada Publishing; 2015. pp. 481-487. ISBN: 978-80247-9902-5 (PDF); 978-80-247-4867-2 (Print) (in Czech) [7] Pocock G, Richards C. Human Physiology The Basis of Medicine. Third ed. Oxford Univer-

[8] Belvisi MG, Stretton DC, Yacoub M, Barnes PJ. Nitric oxide is the endogenous neurotransmitter of bronchodilator nerves in humans. European Journal of Pharmacology. 1992;

[9] Opavský J, Salinger J. Vyšetrovacie metódy dysfunkcie autonómneho nervového systému —Prehľad pre potreby klinické praxe. Non-Invasive Cardiology. 1995;4:139-153. (in Slo-

[10] Sammito S, Sammito W, Bockelmann I. The circadian rhythm of heart rate variability. Biological Rhythm Research. 2016;47(5):717-730. DOI: 10.1080/09291016.2016.1183887

210(2):221-222. DOI: 10.1016/0014-2999(92)90676-U. PMID 1350993

ogy. 5th ed. St. Louis, MO: Mosby; 2004. ISBN 0323022251

sity Press; 2006. p. 63. ISBN: 978-0-19-856878-0

978-1-4051-7344-5

12 Autonomic Nervous System

vak language)

**Chapter 2**

**Provisional chapter**

**Development of Human Pancreatic Innervation**

**Development of Human Pancreatic Innervation**

DOI: 10.5772/intechopen.77089

Human pancreatic innervation is of particular interest due to its possible role in the pathogenesis of such diseases as diabetes mellitus, pancreatitis and pancreatic cancer. Despite the clinical importance, data concerning pancreatic innervation during human ontogeny and in various disorders are very limited. In this chapter, we present a review on human pancreatic autonomic innervation on the basis of the literature data and our previous results. Special attention is paid to the innervation of the endocrine pancreas. Gradual branching of neural network was seen during human pancreatic development. Innervation of the foetal pancreas is more abundant than in adults. In agreement with previous observations, we have revealed a close integration and similarity between endocrine cells and nervous elements in the developing human pancreas. Moreover, simultaneous interactions between the nervous system components, epithelial cells and endocrine cells were detected in the pancreas during prenatal human development. It has been suggested that pancreatic innervation plays an important role not only in regulation

of endocrine and exocrine activity but also in normal islet morphogenesis.

**Keywords:** pancreatic innervation, islets of Langerhans, human development,

The pancreas of most vertebrates is an organ that combines both endocrine and exocrine functions. Functions of the exocrine pancreas are the synthesis, accumulation and secretion of digestive enzymes (protease, amylase, lipase and nucleases) and preferment (elastase, procarboxypeptidase, trypsinogen, pepsinogen, deoxyribonuclease and ribonuclease). The main

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Alexandra E. Proshchina, Yuliya S. Krivova, Olga G. Leonova, Valeriy M. Barabanov and

Alexandra E. Proshchina, Yuliya S. Krivova, Olga G. Leonova, Valeriy M. Barabanov and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

sympathetic system, parasympathetic system

http://dx.doi.org/10.5772/intechopen.77089

Sergey V. Saveliev

**Abstract**

**1. Introduction**

Sergey V. Saveliev

#### **Development of Human Pancreatic Innervation Development of Human Pancreatic Innervation**

DOI: 10.5772/intechopen.77089

Alexandra E. Proshchina, Yuliya S. Krivova, Olga G. Leonova, Valeriy M. Barabanov and Sergey V. Saveliev Alexandra E. Proshchina, Yuliya S. Krivova, Olga G. Leonova, Valeriy M. Barabanov and Sergey V. Saveliev

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77089

#### **Abstract**

Human pancreatic innervation is of particular interest due to its possible role in the pathogenesis of such diseases as diabetes mellitus, pancreatitis and pancreatic cancer. Despite the clinical importance, data concerning pancreatic innervation during human ontogeny and in various disorders are very limited. In this chapter, we present a review on human pancreatic autonomic innervation on the basis of the literature data and our previous results. Special attention is paid to the innervation of the endocrine pancreas. Gradual branching of neural network was seen during human pancreatic development. Innervation of the foetal pancreas is more abundant than in adults. In agreement with previous observations, we have revealed a close integration and similarity between endocrine cells and nervous elements in the developing human pancreas. Moreover, simultaneous interactions between the nervous system components, epithelial cells and endocrine cells were detected in the pancreas during prenatal human development. It has been suggested that pancreatic innervation plays an important role not only in regulation of endocrine and exocrine activity but also in normal islet morphogenesis.

**Keywords:** pancreatic innervation, islets of Langerhans, human development, sympathetic system, parasympathetic system

#### **1. Introduction**

The pancreas of most vertebrates is an organ that combines both endocrine and exocrine functions. Functions of the exocrine pancreas are the synthesis, accumulation and secretion of digestive enzymes (protease, amylase, lipase and nucleases) and preferment (elastase, procarboxypeptidase, trypsinogen, pepsinogen, deoxyribonuclease and ribonuclease). The main

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

function of the endocrine pancreas is regulation of carbohydrate metabolism. Specialised endocrine cells are grouped in units called pancreatic islets or islets of Langerhans. Islets of mammals (including humans) contain four major types of endocrine cells: beta cells secreting insulin, alpha cells secreting glucagon, delta cells secreting somatostatin and PP cells that synthesise pancreatic polypeptide [1]. Recently, another type of pancreatic endocrine cells was described—ghrelin-containing cells (epsilon cells) [2]. Pancreatic innervation is of interest due to its role in the pathogenesis of some diseases including chronic pancreatitis, pancreatic cancer and type 1 diabetes. Pain is the dominant clinical symptom in the majority of cases (73–93%) in patients with pancreatic cancer and pancreatitis. At the same time, the aetiology and pathogenesis of pain in chronic pancreatitis and pancreatic cancer are still unclear and are the subject of numerous studies [3].

identified in the mouse pancreas [18]. Similar data were obtained in studies on the pancreas of the rat and nutria [22, 23]. One of the most interesting features of the mammalian pancreas is that endocrine cells may form highly organised complexes with structures of the nervous system, so-called neuro-insular complexes (NICs). The structure of NIC in the human pancreas has not been studied in detail since their first description by van Campenhout [24] and Simard [25]. Fujita described two types of NIC, which he observed in the foetal and adult pancreas of the dog, cat and rabbit [26]. Some of the pancreatic ganglia contained endocrine cells forming NIC type I (NIC I). In NIC type II (NIC II), endocrine cells lie on the surface of, or even in the midst of, the nerve bundle. However, the distinction between these two types of complexes is conditional because there is an intermediate type of complex in which islets associate with nerve cells and nerve fibres simultaneously. Thus, in the pancreas, endocrine islets are closely associated with a dispersed neural network, which consists of autonomic nerves including sympathetic, parasympathetic and sensory nerves. Unfortunately, because of depth limitations in microscopy, this network cannot be easily portrayed by standard microtome-based two-dimensional (2D) histology. The systematic development of three-dimensional (3D) islet neurohistology has provided insight into neural-islet regulatory mechanisms and the role of

Development of Human Pancreatic Innervation http://dx.doi.org/10.5772/intechopen.77089 17

In addition, endocrine cells of pancreatic islets are similar to nervous cells in some biochemical and physiological characteristics. Some proteins expressed in endocrine cells of pancreatic islets are also specific to the nervous system: S100, GFAP (glial fibrillary acidic protein), GAD (glutamic acid decarboxylase), TH (tyrosine hydroxylase), NPY (neuropeptide Y), NSE (neuron-specific enolase) and others [6, 7, 30–32]. Moreover, a number of transcription factors that are characteristic of the nervous system, such as Ngn3 (neurogenin3), BETA2/NEUROD, etc., are expressed during the differentiation of pancreatic endocrine cells [33–35]. The cells of the endocrine pancreas are classified as cells of a dispersed (diffuse) endocrine epithelial system. The cells of the dispersed endocrine system are a part of the so-called APUD (amine precursor uptake and decarboxylation) system [36]. These cells have the combined ability to the capture and deposit amine precursors and synthesise biogenic amines. The obvious similarity between the pancreatic endocrine cells and nerve tissue leaves the issue of its causes

The precise innervation patterns of islets are unknown, particularly in humans [37]. Every year reviews are published, in which morphology and function of pancreatic innervation are discussed (see for review [10, 11, 14, 15, 38–40]). However, the nature and distribution of the nervous system structures in the pancreas were studied mainly in rodents. Interspecies differences in the structure and innervation of the pancreas between humans and experimental animals (mice and rats) are quite large. In humans, the pancreas is a compact organ, while in rodents it is treelike, distributed over the mesentery of the small intestine. Therefore, it is impossible to automatically transfer the data obtained on experimental animals to humans.

In addition, knowledge about the dynamics of innervation during ontogenesis and in various diseases of the pancreas is very limited. Single studies are devoted to the formation of innervation in prenatal human development (mainly in the last century, without the use of modern methods). Therefore, the fine details of pancreatic innervation (such as the distribution of

neural tissue remodelling in the development of diabetes [27–29].

open to discuss.

In experiments on rodents (mice and rats) and cell cultures, it was indicated that nerve fibres and glial cells located in pancreatic islets may be the first target of autoimmune attack in type 1 diabetes [4–7]. Recently, there were reports of involvement of the peripheral nervous system in the pathogenesis of types 1 and 2 diabetes in humans [8, 9]. Moreover, the participation of the nervous system in the regulation of maturation, level of proliferation and number of insulin-producing beta cells, both in prenatal pancreatic development and in the postnatal period, was indicated in a number of experimental studies. Therefore, detailed information about the innervation of the endocrine pancreas is needed for understanding the mechanisms of beta cell pool renewal.

The pancreas is well innervated by the autonomic nervous system in various mammalian species [3, 10–15]. Rich innervation of the blood vessels and the exocrine part of the pancreas as well a more abundant innervation of the islets compared with the surrounding acinar part was detected already in the early studies [16, 17].

Connections between neurons are usually studied using anterograde and retrograde labelling of pathways. Pancreatic innervation was studied in various animal species using different tracing methods involving viruses, cholera toxin B, horseradish peroxidase, True Blue or DiI. It is believed that nerve fibres enter (and exit) in the pancreas as a part of neurovascular trunks. Within the pancreas, they also pass along the blood vessels and terminate (or, conversely, begin) near to the capillary wall and endocrine cells [18]. At the same time, they do not form classical synapses with target cells, but release neurotransmitters into the intercellular space, thus affecting more than one target simultaneously (i.e. they are enpassant synapses) [14]. Using retrograde labelling, the connection of pancreatic innervation with the central parasympathetic and sympathetic neurons in the brain stem, midbrain, hypothalamus and forebrain was shown [19–21]. Some of these brain centres are involved in monitoring of food intake or circadian rhythms, and it would be logical to assume that they send signals to the pancreas to adapt the digestive ferments and pancreatic hormone secretion to behavioural status. However, the central regulation of these processes has not yet been sufficiently studied [14].

In the pancreas, nerve endings were shown around blood vessels, as well as pancreatic acinar, ductal and endocrine cells, using immunohistochemistry and electron microscopy [17, 18]. Four types of plexuses (perivascular, periductal, periacinar and peri-insular) have been identified in the mouse pancreas [18]. Similar data were obtained in studies on the pancreas of the rat and nutria [22, 23]. One of the most interesting features of the mammalian pancreas is that endocrine cells may form highly organised complexes with structures of the nervous system, so-called neuro-insular complexes (NICs). The structure of NIC in the human pancreas has not been studied in detail since their first description by van Campenhout [24] and Simard [25]. Fujita described two types of NIC, which he observed in the foetal and adult pancreas of the dog, cat and rabbit [26]. Some of the pancreatic ganglia contained endocrine cells forming NIC type I (NIC I). In NIC type II (NIC II), endocrine cells lie on the surface of, or even in the midst of, the nerve bundle. However, the distinction between these two types of complexes is conditional because there is an intermediate type of complex in which islets associate with nerve cells and nerve fibres simultaneously. Thus, in the pancreas, endocrine islets are closely associated with a dispersed neural network, which consists of autonomic nerves including sympathetic, parasympathetic and sensory nerves. Unfortunately, because of depth limitations in microscopy, this network cannot be easily portrayed by standard microtome-based two-dimensional (2D) histology. The systematic development of three-dimensional (3D) islet neurohistology has provided insight into neural-islet regulatory mechanisms and the role of neural tissue remodelling in the development of diabetes [27–29].

function of the endocrine pancreas is regulation of carbohydrate metabolism. Specialised endocrine cells are grouped in units called pancreatic islets or islets of Langerhans. Islets of mammals (including humans) contain four major types of endocrine cells: beta cells secreting insulin, alpha cells secreting glucagon, delta cells secreting somatostatin and PP cells that synthesise pancreatic polypeptide [1]. Recently, another type of pancreatic endocrine cells was described—ghrelin-containing cells (epsilon cells) [2]. Pancreatic innervation is of interest due to its role in the pathogenesis of some diseases including chronic pancreatitis, pancreatic cancer and type 1 diabetes. Pain is the dominant clinical symptom in the majority of cases (73–93%) in patients with pancreatic cancer and pancreatitis. At the same time, the aetiology and pathogenesis of pain in chronic pancreatitis and pancreatic cancer are still unclear and are

In experiments on rodents (mice and rats) and cell cultures, it was indicated that nerve fibres and glial cells located in pancreatic islets may be the first target of autoimmune attack in type 1 diabetes [4–7]. Recently, there were reports of involvement of the peripheral nervous system in the pathogenesis of types 1 and 2 diabetes in humans [8, 9]. Moreover, the participation of the nervous system in the regulation of maturation, level of proliferation and number of insulin-producing beta cells, both in prenatal pancreatic development and in the postnatal period, was indicated in a number of experimental studies. Therefore, detailed information about the innervation of the endocrine pancreas is needed for understanding the mechanisms

The pancreas is well innervated by the autonomic nervous system in various mammalian species [3, 10–15]. Rich innervation of the blood vessels and the exocrine part of the pancreas as well a more abundant innervation of the islets compared with the surrounding acinar part

Connections between neurons are usually studied using anterograde and retrograde labelling of pathways. Pancreatic innervation was studied in various animal species using different tracing methods involving viruses, cholera toxin B, horseradish peroxidase, True Blue or DiI. It is believed that nerve fibres enter (and exit) in the pancreas as a part of neurovascular trunks. Within the pancreas, they also pass along the blood vessels and terminate (or, conversely, begin) near to the capillary wall and endocrine cells [18]. At the same time, they do not form classical synapses with target cells, but release neurotransmitters into the intercellular space, thus affecting more than one target simultaneously (i.e. they are enpassant synapses) [14]. Using retrograde labelling, the connection of pancreatic innervation with the central parasympathetic and sympathetic neurons in the brain stem, midbrain, hypothalamus and forebrain was shown [19–21]. Some of these brain centres are involved in monitoring of food intake or circadian rhythms, and it would be logical to assume that they send signals to the pancreas to adapt the digestive ferments and pancreatic hormone secretion to behavioural status. However, the central regulation of these processes has not yet been suf-

In the pancreas, nerve endings were shown around blood vessels, as well as pancreatic acinar, ductal and endocrine cells, using immunohistochemistry and electron microscopy [17, 18]. Four types of plexuses (perivascular, periductal, periacinar and peri-insular) have been

the subject of numerous studies [3].

16 Autonomic Nervous System

of beta cell pool renewal.

ficiently studied [14].

was detected already in the early studies [16, 17].

In addition, endocrine cells of pancreatic islets are similar to nervous cells in some biochemical and physiological characteristics. Some proteins expressed in endocrine cells of pancreatic islets are also specific to the nervous system: S100, GFAP (glial fibrillary acidic protein), GAD (glutamic acid decarboxylase), TH (tyrosine hydroxylase), NPY (neuropeptide Y), NSE (neuron-specific enolase) and others [6, 7, 30–32]. Moreover, a number of transcription factors that are characteristic of the nervous system, such as Ngn3 (neurogenin3), BETA2/NEUROD, etc., are expressed during the differentiation of pancreatic endocrine cells [33–35]. The cells of the endocrine pancreas are classified as cells of a dispersed (diffuse) endocrine epithelial system. The cells of the dispersed endocrine system are a part of the so-called APUD (amine precursor uptake and decarboxylation) system [36]. These cells have the combined ability to the capture and deposit amine precursors and synthesise biogenic amines. The obvious similarity between the pancreatic endocrine cells and nerve tissue leaves the issue of its causes open to discuss.

The precise innervation patterns of islets are unknown, particularly in humans [37]. Every year reviews are published, in which morphology and function of pancreatic innervation are discussed (see for review [10, 11, 14, 15, 38–40]). However, the nature and distribution of the nervous system structures in the pancreas were studied mainly in rodents. Interspecies differences in the structure and innervation of the pancreas between humans and experimental animals (mice and rats) are quite large. In humans, the pancreas is a compact organ, while in rodents it is treelike, distributed over the mesentery of the small intestine. Therefore, it is impossible to automatically transfer the data obtained on experimental animals to humans.

In addition, knowledge about the dynamics of innervation during ontogenesis and in various diseases of the pancreas is very limited. Single studies are devoted to the formation of innervation in prenatal human development (mainly in the last century, without the use of modern methods). Therefore, the fine details of pancreatic innervation (such as the distribution of sympathetic and parasympathetic fibres and the formation of neuro-insular complexes) in human ontogenesis are insufficiently studied. This is mainly due to the inaccessibility of the material and to a number of technical difficulties, including the quality of pancreatic autopsy samples due to the activity of enzymes of the exocrine part [40].

In humans, the body and tail of the pancreas are innervated by nerve fibres originating from the ventral plexus and accompanying two arteries: the splenic artery and the transverse artery of the pancreas. The pancreatic head receives the largest number of nerve fibres [57, 58].

Development of Human Pancreatic Innervation http://dx.doi.org/10.5772/intechopen.77089 19

In the exocrine pancreas, sympathetic axons contact mostly with intrapancreatic ganglia, blood vessels and ducts. In mice, the innervation of the exocrine part is less pronounced than in humans. The major nerves run along the interlobular arteries and form the peri-insular plexus [18]. At the same time, in mice axons of sympathetic nerves contact alpha cells, while contact with beta cells is not found [44]. The axons of sympathetic nerves also innervate smooth muscle cells and pericytes of blood vessels and perivascular space, forming the socalled sympathetic neurovascular complex. In humans, sympathetic fibres innervate smooth muscle cells and pericytes and rarely contact directly with the endocrine cells. Apparently, the effects of the sympathetic innervation are likely mediated through indirect effects on local

The bodies of the neurons forming the parasympathetic preganglionic nerve fibres lie in the dorsal motor nucleus of the n. vagus (X) [60–62] and, possibly, in the *nucleus ambiguus* [11–13]. Both of these nuclei are under the control of the hypothalamus. Preganglionic parasympathetic fibres are directed to the pancreas as a part of the vagus nerve branches. In the pancreas, parasympathetic fibres terminate on the bodies of parasympathetic neurons lying in intrapancreatic ganglia [38, 63]. These ganglia contain from 3 to 30 neurons and are usually located in intralobular connective tissue, within lobules or in close proximity to islets [13, 27, 29]. It is also important that these ganglia receive input not only from the parasympathetic nervous system but also from the sympathetic nervous system, as well as fibres from other intrapancreatic ganglia and also from the *myenteric plexus* [13]. Parasympathetic fibres are also involved in the formation of nerve plexuses around the arteries and mingle with sympathetic fibres.

Preganglionic parasympathetic fibres secrete acetylcholine (Ach), which binds to nicotine receptors on the membranes of neurons [53]. Short, unmyelinated postganglionic fibres terminate on the epithelial cells of acini and ducts, smooth muscle cells and islet cells. Postganglionic parasympathetic fibres release several neurotransmitters (Ach (acetylcholine) and NO (nitric oxide)) and neuropeptides (VIP (vasoactive intestinal peptide), GRP (gastrin-releasing peptide) and PACAP (pituitary-activating adenyl cyclase polypeptide)) [10, 11, 13, 56]. Postganglionic nerve fibres perform their functions mainly via Ach by binding to muscarinic receptors found, in particular, in the endocrine cells of the islets [12, 53]. In mice, postganglionic parasympathetic nerve fibres innervate all types of islets cells [10, 11, 44]. Recently, it was found that parasympathetic islet innervation in humans differs from that in mice: first, it was shown that only a small number of fibres penetrate inside the islets (most of the axons terminate in the exocrine part of the pancreas) [44], and, secondly, it was recently shown that stimulation with Ach mostly stimulates beta and delta cells, whereas alpha cells react to a lesser extent [64]. Interestingly, alpha cells themselves may be the primary source of Ach in human islets [45]. Apparently, in human islets, this classical neurotransmitter regulates the activity of other cell types in a paracrine manner. However, now, this concept is again under

blood flow within the islet microcirculation [44, 59].

revision thanks recently to the work of Tang et al. [29].

**2.2. Efferent parasympathetic fibres**

However, over the past 10 years, different groups of researchers have made significant progress in the study of the peculiarities of innervation in rodents. The most attention was paid to the influence of the nervous system on the endocrine pancreas. It has been shown that both sympathetic and parasympathetic nervous systems affect postnatal development of the endocrine pancreas and its plasticity in adult animals [9, 41]. For example, after vagotomy there was a decrease in insulin-containing cell proliferation in mice and rats [42]. The important role of the sympathetic innervation for the formation of islet cytoarchitecture and their functional maturation during development was also shown [43].

Thanks to recent progresses in the field of islet research (including the study of isolated islets, in thick slices and in vivo), a number of issues concerning the structure and functions of pancreatic innervation have been clarified (see, e.g. [44–47]). In this chapter, we summarise the literature data and our previous results concerning the morphological organisation of autonomic innervation in the human foetal and adult pancreas. We also discuss the possible role of the close integration between the nervous system and epithelial and endocrine cells in the development of the endocrine pancreas.

#### **2. Sources of pancreatic innervation**

The pancreas is innervated by sympathetic and parasympathetic nerve fibres [11, 13]. The literature data indicate poor innervation of adult human pancreatic islets in comparison with rodents [44, 48–50]. At the end of the twentieth century, pancreatic innervation by postganglionic adrenergic and cholinergic fibres was intensively studied (for references, see [51]). Single nerve cells and nerve ganglia, both myelinated and unmyelinated nerve fibres of various diameters, have been detected in the human pancreas [23, 37, 48, 49]. In a simplified form, it can be considered that pancreatic sympathetic innervation is effected by the fibres of the ventral trunk and the parasympathetic innervation by the vagus nerve.

#### **2.1. Efferent sympathetic fibres**

Bodies of neurons, which form the efferent preganglionic sympathetic nerve fibres, are localised in the thoracic and upper lumbar segments of the spinal cord (T5–L1) [37, 52] or, according to some literature, in C8–L3 [21, 53]. Myelinated axons of these cells leave the ventral roots of the spinal cord and terminate on the bodies of neurons that lie in the ganglia of the paravertebral sympathetic chain, or pass through this chain via the n. splanchnicus to the celiac (*celiac*) and superior mesenteric (*mesenteric*) ganglia, and then terminate on neurons localised in these ganglia [54, 55]. The preganglionic fibres of the sympathetic system secrete acetylcholine (Ach). Postganglionic nerve fibres go to the pancreas, where they secrete norepinephrine, which binds to α and β adrenergic receptors and the neuropeptides galanin and NPY (neuropeptide Y) [10, 11, 53, 56].

In humans, the body and tail of the pancreas are innervated by nerve fibres originating from the ventral plexus and accompanying two arteries: the splenic artery and the transverse artery of the pancreas. The pancreatic head receives the largest number of nerve fibres [57, 58].

In the exocrine pancreas, sympathetic axons contact mostly with intrapancreatic ganglia, blood vessels and ducts. In mice, the innervation of the exocrine part is less pronounced than in humans. The major nerves run along the interlobular arteries and form the peri-insular plexus [18]. At the same time, in mice axons of sympathetic nerves contact alpha cells, while contact with beta cells is not found [44]. The axons of sympathetic nerves also innervate smooth muscle cells and pericytes of blood vessels and perivascular space, forming the socalled sympathetic neurovascular complex. In humans, sympathetic fibres innervate smooth muscle cells and pericytes and rarely contact directly with the endocrine cells. Apparently, the effects of the sympathetic innervation are likely mediated through indirect effects on local blood flow within the islet microcirculation [44, 59].

#### **2.2. Efferent parasympathetic fibres**

sympathetic and parasympathetic fibres and the formation of neuro-insular complexes) in human ontogenesis are insufficiently studied. This is mainly due to the inaccessibility of the material and to a number of technical difficulties, including the quality of pancreatic autopsy

However, over the past 10 years, different groups of researchers have made significant progress in the study of the peculiarities of innervation in rodents. The most attention was paid to the influence of the nervous system on the endocrine pancreas. It has been shown that both sympathetic and parasympathetic nervous systems affect postnatal development of the endocrine pancreas and its plasticity in adult animals [9, 41]. For example, after vagotomy there was a decrease in insulin-containing cell proliferation in mice and rats [42]. The important role of the sympathetic innervation for the formation of islet cytoarchitecture and their func-

Thanks to recent progresses in the field of islet research (including the study of isolated islets, in thick slices and in vivo), a number of issues concerning the structure and functions of pancreatic innervation have been clarified (see, e.g. [44–47]). In this chapter, we summarise the literature data and our previous results concerning the morphological organisation of autonomic innervation in the human foetal and adult pancreas. We also discuss the possible role of the close integration between the nervous system and epithelial and endocrine cells in the

The pancreas is innervated by sympathetic and parasympathetic nerve fibres [11, 13]. The literature data indicate poor innervation of adult human pancreatic islets in comparison with rodents [44, 48–50]. At the end of the twentieth century, pancreatic innervation by postganglionic adrenergic and cholinergic fibres was intensively studied (for references, see [51]). Single nerve cells and nerve ganglia, both myelinated and unmyelinated nerve fibres of various diameters, have been detected in the human pancreas [23, 37, 48, 49]. In a simplified form, it can be considered that pancreatic sympathetic innervation is effected by the fibres of the

Bodies of neurons, which form the efferent preganglionic sympathetic nerve fibres, are localised in the thoracic and upper lumbar segments of the spinal cord (T5–L1) [37, 52] or, according to some literature, in C8–L3 [21, 53]. Myelinated axons of these cells leave the ventral roots of the spinal cord and terminate on the bodies of neurons that lie in the ganglia of the paravertebral sympathetic chain, or pass through this chain via the n. splanchnicus to the celiac (*celiac*) and superior mesenteric (*mesenteric*) ganglia, and then terminate on neurons localised in these ganglia [54, 55]. The preganglionic fibres of the sympathetic system secrete acetylcholine (Ach). Postganglionic nerve fibres go to the pancreas, where they secrete norepinephrine, which binds to α and β adrenergic receptors and the neuropeptides galanin and

ventral trunk and the parasympathetic innervation by the vagus nerve.

samples due to the activity of enzymes of the exocrine part [40].

tional maturation during development was also shown [43].

development of the endocrine pancreas.

18 Autonomic Nervous System

**2.1. Efferent sympathetic fibres**

NPY (neuropeptide Y) [10, 11, 53, 56].

**2. Sources of pancreatic innervation**

The bodies of the neurons forming the parasympathetic preganglionic nerve fibres lie in the dorsal motor nucleus of the n. vagus (X) [60–62] and, possibly, in the *nucleus ambiguus* [11–13]. Both of these nuclei are under the control of the hypothalamus. Preganglionic parasympathetic fibres are directed to the pancreas as a part of the vagus nerve branches. In the pancreas, parasympathetic fibres terminate on the bodies of parasympathetic neurons lying in intrapancreatic ganglia [38, 63]. These ganglia contain from 3 to 30 neurons and are usually located in intralobular connective tissue, within lobules or in close proximity to islets [13, 27, 29]. It is also important that these ganglia receive input not only from the parasympathetic nervous system but also from the sympathetic nervous system, as well as fibres from other intrapancreatic ganglia and also from the *myenteric plexus* [13]. Parasympathetic fibres are also involved in the formation of nerve plexuses around the arteries and mingle with sympathetic fibres.

Preganglionic parasympathetic fibres secrete acetylcholine (Ach), which binds to nicotine receptors on the membranes of neurons [53]. Short, unmyelinated postganglionic fibres terminate on the epithelial cells of acini and ducts, smooth muscle cells and islet cells. Postganglionic parasympathetic fibres release several neurotransmitters (Ach (acetylcholine) and NO (nitric oxide)) and neuropeptides (VIP (vasoactive intestinal peptide), GRP (gastrin-releasing peptide) and PACAP (pituitary-activating adenyl cyclase polypeptide)) [10, 11, 13, 56]. Postganglionic nerve fibres perform their functions mainly via Ach by binding to muscarinic receptors found, in particular, in the endocrine cells of the islets [12, 53]. In mice, postganglionic parasympathetic nerve fibres innervate all types of islets cells [10, 11, 44]. Recently, it was found that parasympathetic islet innervation in humans differs from that in mice: first, it was shown that only a small number of fibres penetrate inside the islets (most of the axons terminate in the exocrine part of the pancreas) [44], and, secondly, it was recently shown that stimulation with Ach mostly stimulates beta and delta cells, whereas alpha cells react to a lesser extent [64]. Interestingly, alpha cells themselves may be the primary source of Ach in human islets [45]. Apparently, in human islets, this classical neurotransmitter regulates the activity of other cell types in a paracrine manner. However, now, this concept is again under revision thanks recently to the work of Tang et al. [29].

#### **2.3. The afferent fibres**

In the pancreas, there are afferent (sensory) nerve fibres in addition to efferent sympathetic and parasympathetic innervation [10–12, 53, 54]. Bundles of sensory nerve fibres leave the pancreas and follow the sympathetic (*n. splanchnicus*) and vagus nerves. The bodies of sensory sympathetic neurons are localised in the ganglia of the dorsal roots in the spinal cord, mainly at the level of the lower thoracic segments (the so-called spinal afferents) projected on interneuron plates I and IV [52, 65]. For the parasympathetic system, the bodies of afferent neurons are localised in the ganglion nodosum, sending information to the nucleus of tractus solitarii [12, 54]. The neurotransmitters of the sensory nerve fibres are CGRP (calcitonin generelated peptide) and SP (substance P). Most sympathetic and parasympathetic afferent nerves are sensitive to capsaicin [14]. Capsaicin (vanillin) receptors mainly transmit pain information [66]. In addition, Pacinian corpuscles were described in the pancreas of various mammalian species. The suggested function of this receptor is to transmit information about pressure and vibration stimuli. In the human pancreas, they were discovered in the early twentieth century [67]. Despite this fact being presented in many histology textbooks, in the modern literature, only three cases of these findings (all in pancreatic cancer) were described [67, 68]. In our research, we have studied pancreatic autopsies of 42 foetuses and neonates aged from the 10th to 40th week of gestation and of 65 adults, 18 of whom suffered from diabetes mellitus type 2. In total, more than 1000 sections were investigated. However, Pacinian corpuscles are a rare finding in the human pancreas: we were able to detect Pacinian corpuscles only in one pancreatic section of a newborn with diagnosed diabetic fetopathy. Thus, Pacinian corpuscles do not appear to play a significant role in the sensory innervation of the human pancreas.

The complex structure of the enteric nervous system, containing a variety of morphological and functional types of neurons and their neurotransmitters, allows the ENS to perform complex reflex acts, some of which are implemented autonomously and some in interaction with the central nervous system and other parts of the autonomous nervous system. Intrapancreatic ganglia are connected with autonomous ganglia in the intestinal nerve plexus [71–73]. Neurotransmitters for neurons of these ganglia are, among others, serotonin and nitric oxide (NO) [73]. However, according the dominant viewpoint, intramural pancreatic

Development of Human Pancreatic Innervation http://dx.doi.org/10.5772/intechopen.77089 21

As was mentioned earlier, the pancreas combines exo- and endocrine functions, secreting digestive enzymes and hormones, which regulate glucose homeostasis. The nervous system regulates the activity of both the endocrine and exocrine pancreas. However, it is problematic to separate the innervation of the pancreatic endocrine part from the innervation of the exocrine, since the tracing method used for this purpose belongs to the pancreas as a whole. In addition, the activity of both endocrine and exocrine parts of the pancreas depends on food intake. Therefore, it is not surprising that the cephalic phase has been described for both pancreatic parts. Although the stimulation of the ventromedial hypothalamus and efferent sympathetic and parasympathetic neurons affects the secretion of islet hormones (see below), it is unknown whether this stimulation is direct through axons innervating the islet or indirect by activating other organs, which affect insulin and glucagon secretion [14]. Moreover, it is very

difficult to separate the nervous system effects from other (e.g. humoral) influences.

"chemical messenger" identified. This type of substance is now called a hormone.

(nervous and humoral) act simultaneously and synergistically.

So, in the laboratory of I.P. Pavlov, in 1895, I.L. Dolinsky conducted an experiment in which he established that acid injection into the duodenum causes a release of pancreatic juice [74]. In 1901, British physiologists William Baileys and Ernest Starling concluded that there is some substance released by the duodenum that stimulates secretion by the pancreas. In the following year, 1902, this substance was discovered and named secretin. Secretin was the first such

At the same time, in the classic studies of I. P. Pavlov with M. A. Afanasiev, the nervous mechanism of pancreatic secretion was found. In the work "On secretory nerves of the pancreas" (1877), they showed that vagus nerve stimulation causes pancreatic secretion. Moreover, I. P. Pavlov with his colleagues detected that imaginary feeding in animals with chronic pancreatic fistula causes an abundant release of pancreatic juice. Later, this was confirmed by the studies of K. M. Bykov and G. M. Davydov in patients with pancreatic fistula. An abundant pancreatic juice released by this patient occurred while talking about delicious food [74]. However, pancreatic juice obtained after vagus nerve stimulation is released in a small quantity and is rich in proteins and enzymes, whereas after the secretin injection, it contains little proteins and enzymes and is released in large quantities [74]. It should be noted that both these factors

neurons belong to the parasympathetic system.

**3. Functional role of pancreatic innervation**

#### **2.4. Enteric nervous system**

In some studies on pancreatic innervation, it is assumed that the pancreas is innervated not only by extrinsic efferent and afferent nerves but also by intrinsic enteric neurons of the socalled enteric nervous system (ENS) [12, 69]. The ENS controls the motor, secretion and other functions of the gastrointestinal tract and is closely related with the diffuse endocrine system [70]. Enteric ganglia have some morphological and functional differences from sympathetic and parasympathetic ganglia:


The complex structure of the enteric nervous system, containing a variety of morphological and functional types of neurons and their neurotransmitters, allows the ENS to perform complex reflex acts, some of which are implemented autonomously and some in interaction with the central nervous system and other parts of the autonomous nervous system. Intrapancreatic ganglia are connected with autonomous ganglia in the intestinal nerve plexus [71–73]. Neurotransmitters for neurons of these ganglia are, among others, serotonin and nitric oxide (NO) [73]. However, according the dominant viewpoint, intramural pancreatic neurons belong to the parasympathetic system.

#### **3. Functional role of pancreatic innervation**

**2.3. The afferent fibres**

20 Autonomic Nervous System

**2.4. Enteric nervous system**

and parasympathetic ganglia:

astrocytes of the CNS.

of the central nervous system, are produce.

not all researchers agree with its existence.

In the pancreas, there are afferent (sensory) nerve fibres in addition to efferent sympathetic and parasympathetic innervation [10–12, 53, 54]. Bundles of sensory nerve fibres leave the pancreas and follow the sympathetic (*n. splanchnicus*) and vagus nerves. The bodies of sensory sympathetic neurons are localised in the ganglia of the dorsal roots in the spinal cord, mainly at the level of the lower thoracic segments (the so-called spinal afferents) projected on interneuron plates I and IV [52, 65]. For the parasympathetic system, the bodies of afferent neurons are localised in the ganglion nodosum, sending information to the nucleus of tractus solitarii [12, 54]. The neurotransmitters of the sensory nerve fibres are CGRP (calcitonin generelated peptide) and SP (substance P). Most sympathetic and parasympathetic afferent nerves are sensitive to capsaicin [14]. Capsaicin (vanillin) receptors mainly transmit pain information [66]. In addition, Pacinian corpuscles were described in the pancreas of various mammalian species. The suggested function of this receptor is to transmit information about pressure and vibration stimuli. In the human pancreas, they were discovered in the early twentieth century [67]. Despite this fact being presented in many histology textbooks, in the modern literature, only three cases of these findings (all in pancreatic cancer) were described [67, 68]. In our research, we have studied pancreatic autopsies of 42 foetuses and neonates aged from the 10th to 40th week of gestation and of 65 adults, 18 of whom suffered from diabetes mellitus type 2. In total, more than 1000 sections were investigated. However, Pacinian corpuscles are a rare finding in the human pancreas: we were able to detect Pacinian corpuscles only in one pancreatic section of a newborn with diagnosed diabetic fetopathy. Thus, Pacinian corpuscles do not appear to play a significant role in the sensory innervation of the human pancreas.

In some studies on pancreatic innervation, it is assumed that the pancreas is innervated not only by extrinsic efferent and afferent nerves but also by intrinsic enteric neurons of the socalled enteric nervous system (ENS) [12, 69]. The ENS controls the motor, secretion and other functions of the gastrointestinal tract and is closely related with the diffuse endocrine system [70]. Enteric ganglia have some morphological and functional differences from sympathetic

**1.** The ENS performs complex integrative functions independently of higher nerve centres. **2.** In the ENS, a large number of various neurotransmitters, many of which are characteristic

**3.** Unlike other autonomous ganglia, enteric ganglia do not contain connective tissue and blood vessels. Enteric ganglia are demarcated from the surrounding tissue of the so-called blood-ganglionic barrier, similar to the blood–brain barrier. It is insufficiently studied, and

**4.** Glial cells of enteric ganglia are similar in morphology, cell markers and functions with

As was mentioned earlier, the pancreas combines exo- and endocrine functions, secreting digestive enzymes and hormones, which regulate glucose homeostasis. The nervous system regulates the activity of both the endocrine and exocrine pancreas. However, it is problematic to separate the innervation of the pancreatic endocrine part from the innervation of the exocrine, since the tracing method used for this purpose belongs to the pancreas as a whole. In addition, the activity of both endocrine and exocrine parts of the pancreas depends on food intake. Therefore, it is not surprising that the cephalic phase has been described for both pancreatic parts. Although the stimulation of the ventromedial hypothalamus and efferent sympathetic and parasympathetic neurons affects the secretion of islet hormones (see below), it is unknown whether this stimulation is direct through axons innervating the islet or indirect by activating other organs, which affect insulin and glucagon secretion [14]. Moreover, it is very difficult to separate the nervous system effects from other (e.g. humoral) influences.

So, in the laboratory of I.P. Pavlov, in 1895, I.L. Dolinsky conducted an experiment in which he established that acid injection into the duodenum causes a release of pancreatic juice [74]. In 1901, British physiologists William Baileys and Ernest Starling concluded that there is some substance released by the duodenum that stimulates secretion by the pancreas. In the following year, 1902, this substance was discovered and named secretin. Secretin was the first such "chemical messenger" identified. This type of substance is now called a hormone.

At the same time, in the classic studies of I. P. Pavlov with M. A. Afanasiev, the nervous mechanism of pancreatic secretion was found. In the work "On secretory nerves of the pancreas" (1877), they showed that vagus nerve stimulation causes pancreatic secretion. Moreover, I. P. Pavlov with his colleagues detected that imaginary feeding in animals with chronic pancreatic fistula causes an abundant release of pancreatic juice. Later, this was confirmed by the studies of K. M. Bykov and G. M. Davydov in patients with pancreatic fistula. An abundant pancreatic juice released by this patient occurred while talking about delicious food [74]. However, pancreatic juice obtained after vagus nerve stimulation is released in a small quantity and is rich in proteins and enzymes, whereas after the secretin injection, it contains little proteins and enzymes and is released in large quantities [74]. It should be noted that both these factors (nervous and humoral) act simultaneously and synergistically.

Currently, it is considered that efferent sympathetic nerve fibres indirectly inhibit the release of enzymes of the exocrine pancreas by suppressing the stimulating effects of ganglia and constriction of vessels (vasoconstriction), thereby reducing blood flow [13, 59]. The stimulation of short, unmyelinated postganglionic parasympathetic fibres increases release from secretory cells of the exocrine pancreas and ducts causing vasodilation [13, 57].

nerve fibres are detected within islets. The bodies of ganglion neurons are also rarely localised in the pancreatic islets and may be in direct contact with endocrine cells [17, 27, 29, 78, 79].

Development of Human Pancreatic Innervation http://dx.doi.org/10.5772/intechopen.77089 23

It is believed that autonomic innervations indirectly affect the release of insulin in the cephalic phase during food intake and also take part in the increase of glucagon and decrease of insulin release by sympathetic stimulation [10, 80]. Stimulation of the splanchnic nerve increases the release of glucagon and reduces the release of insulin and somatostatin from endocrine cells of the pancreas [12, 14, 15]. Sympathetic nerves are also believed to be involved in islet response for hypoglycemia, which includes increased glucagon secretion and inhibition of insulin secretion. The general sympathetic effect is expressed by reducing the insulin concentration in plasma (by increasing the concentration of catecholamines that inhibit insulin

Parasympathetic nerves are responsible for the early phase of insulin secretion, including the cephalic phase (i.e. insulin secretion, which occurs during anticipation of eating). In general, parasympathetic stimulation is believed to increase the release of insulin, glucagon, somatostatin and pancreatic polypeptide in many different species (for review, see [10, 11, 14, 15]). Sensory nerves are also involved in the regulation of hormone secretion by endocrine cells [11]. Following chemical destruction of sensory nerves (capsaicin treatment) in mice, there is

In conclusion, it should be added that pancreatic innervation is insufficiently studied, especially in humans [40, 44]. Interestingly, the innervation of the islets is very plastic: it has been shown that islets transplanted into the portal vein of diabetic rats were reinnervated by the nerves of the liver [82]. This makes it necessary to further study the role of innervation in the

Despite the clinical importance, data concerning pancreatic innervation during human ontogeny and in diseases are very limited [37]. Such studies have been performed on rodents and mostly concern the sympathetic innervation [43, 55, 83]. The embryonic sources of neural elements are fibres of the vagus (*n. vagus*) and splanchnic nerves (*n. splanchnicus*) growing into the developing pancreas and neurons that differentiate from the neural crest cells migrating to the pancreas. Sympathetic fibres innervate the developing mouse pancreas starting from the 15th day of embryonic development (E14.5) [43]. Consequently, the degree of sympathetic innervation increases until 20 days of postnatal development (P20) [55]. The development of

regulation of glucose homeostasis and plasticity of the endocrine part of the pancreas.

the pancreatic sympathetic innervation depends on nerve growth factor (NGF) [43].

The human pancreas receives extensive innervation, showing peculiar growth dynamics during gestation [37]. Ingrowths of nerves in the human pancreas start at 6 weeks of development. Further morphogenesis of pancreatic innervation is characterised by the increase of sources of innervation and degree of nervous element differentiation [84, 85]. Large bundles of nerve fibres and groups of poorly differentiated neurons are found in the human pancreas

**4. Pancreatic innervation during prenatal development**

an increase in insulin secretion in response to glucose compared to control [81].

secretion) [10, 11].

The autonomous nervous system also regulates hormone release in the endocrine pancreas, thereby affecting glucose metabolism [10, 11, 14, 53]. Many various chemical factors affect insulin and glucagon expression. Auto-, juxta-, para- and endocrine ways potentially regulate secretion of islet hormones. Since the classical studies of Claude Bernard, which showed that injection into the floor of the fourth ventricle causes hyperglycemia, the involvement of the nervous system in the regulation of pancreatic endocrine function and metabolic control has been shown in many studies. It is, therefore, rather difficult to separate one effect from the other [14, 53].

The cellular architecture of islets affects paracrine regulation and synchronises the release of insulin [75]. All pancreatic islets secrete hormones consistently, with an approximately 5-min interval [76]. In order to create this secretion pattern, the activity of insulin-containing beta cells must be consistent both within the individual islet and between the islets [14]. At the same time, the secretory activity of other islets endocrine cells, such as glucagon-secreting alpha cells that have opposite effects on glucose homeostasis, should be consistent with the activity of beta cells. Thanks to this interaction, endocrine cells can simultaneously send signals regulating the effective delivery of islet hormones into the circulatory system and, ultimately, to the liver, regulating the maintenance of glucose homeostasis [76].

However, the islets of Langerhans are a part of a complex coherent system. They are also exposed to humoral factors such as circulating plasma hormones (e.g. epinephrine). The brain also regulates the secretion of islet hormones via the autonomic nervous system [14]. Thus, in works by Akmaev et al. [19], it was shown that the hypothalamus is able to stimulate insulin secretion from beta cells of pancreatic islets along the nerve pathway, which was named "paraventricular-vagal." This pathway starts from small neurons of the paraventricular nucleus (PVN) of the hypothalamus, synaptically switches in the medulla oblongata to neurons of the dorsal nucleus of the vagus nerve and reaches the pancreatic islets in the composition of the vagus nerve. In this pathway, beta cells receive stimulating signals. Inhibitory signals come from neurons by a humoral way: PVN neurons secrete corticotropin-releasing hormone, which stimulates the secretion of adrenocorticotropic hormone in the pituitary gland that induces the secretion of glucocorticoids in the adrenal cortex. Glucocorticoids inhibit insulin release from beta cells. This kind of double control, according to the authors, is typical for the regulation of endocrine functions. Recently, there has been data that significantly complements this concept: various areas of the hypothalamus have different effects on the secretion of insulin and/or glucagon [77]. So, a detailed study of this system is needed to further identify both neurons and functionally related projections of the central nervous system regulating islet functions.

For most species studied, it is characteristic that nerve fibres are localised mainly at the periphery of the pancreatic islets, forming a peri-insular nervous network [17]. Only single nerve fibres are detected within islets. The bodies of ganglion neurons are also rarely localised in the pancreatic islets and may be in direct contact with endocrine cells [17, 27, 29, 78, 79].

Currently, it is considered that efferent sympathetic nerve fibres indirectly inhibit the release of enzymes of the exocrine pancreas by suppressing the stimulating effects of ganglia and constriction of vessels (vasoconstriction), thereby reducing blood flow [13, 59]. The stimulation of short, unmyelinated postganglionic parasympathetic fibres increases release from

The autonomous nervous system also regulates hormone release in the endocrine pancreas, thereby affecting glucose metabolism [10, 11, 14, 53]. Many various chemical factors affect insulin and glucagon expression. Auto-, juxta-, para- and endocrine ways potentially regulate secretion of islet hormones. Since the classical studies of Claude Bernard, which showed that injection into the floor of the fourth ventricle causes hyperglycemia, the involvement of the nervous system in the regulation of pancreatic endocrine function and metabolic control has been shown in many studies. It is, therefore, rather difficult to separate one effect from the

The cellular architecture of islets affects paracrine regulation and synchronises the release of insulin [75]. All pancreatic islets secrete hormones consistently, with an approximately 5-min interval [76]. In order to create this secretion pattern, the activity of insulin-containing beta cells must be consistent both within the individual islet and between the islets [14]. At the same time, the secretory activity of other islets endocrine cells, such as glucagon-secreting alpha cells that have opposite effects on glucose homeostasis, should be consistent with the activity of beta cells. Thanks to this interaction, endocrine cells can simultaneously send signals regulating the effective delivery of islet hormones into the circulatory system and, ulti-

However, the islets of Langerhans are a part of a complex coherent system. They are also exposed to humoral factors such as circulating plasma hormones (e.g. epinephrine). The brain also regulates the secretion of islet hormones via the autonomic nervous system [14]. Thus, in works by Akmaev et al. [19], it was shown that the hypothalamus is able to stimulate insulin secretion from beta cells of pancreatic islets along the nerve pathway, which was named "paraventricular-vagal." This pathway starts from small neurons of the paraventricular nucleus (PVN) of the hypothalamus, synaptically switches in the medulla oblongata to neurons of the dorsal nucleus of the vagus nerve and reaches the pancreatic islets in the composition of the vagus nerve. In this pathway, beta cells receive stimulating signals. Inhibitory signals come from neurons by a humoral way: PVN neurons secrete corticotropin-releasing hormone, which stimulates the secretion of adrenocorticotropic hormone in the pituitary gland that induces the secretion of glucocorticoids in the adrenal cortex. Glucocorticoids inhibit insulin release from beta cells. This kind of double control, according to the authors, is typical for the regulation of endocrine functions. Recently, there has been data that significantly complements this concept: various areas of the hypothalamus have different effects on the secretion of insulin and/or glucagon [77]. So, a detailed study of this system is needed to further identify both neurons and functionally related projections of the central nervous

For most species studied, it is characteristic that nerve fibres are localised mainly at the periphery of the pancreatic islets, forming a peri-insular nervous network [17]. Only single

secretory cells of the exocrine pancreas and ducts causing vasodilation [13, 57].

mately, to the liver, regulating the maintenance of glucose homeostasis [76].

other [14, 53].

22 Autonomic Nervous System

system regulating islet functions.

It is believed that autonomic innervations indirectly affect the release of insulin in the cephalic phase during food intake and also take part in the increase of glucagon and decrease of insulin release by sympathetic stimulation [10, 80]. Stimulation of the splanchnic nerve increases the release of glucagon and reduces the release of insulin and somatostatin from endocrine cells of the pancreas [12, 14, 15]. Sympathetic nerves are also believed to be involved in islet response for hypoglycemia, which includes increased glucagon secretion and inhibition of insulin secretion. The general sympathetic effect is expressed by reducing the insulin concentration in plasma (by increasing the concentration of catecholamines that inhibit insulin secretion) [10, 11].

Parasympathetic nerves are responsible for the early phase of insulin secretion, including the cephalic phase (i.e. insulin secretion, which occurs during anticipation of eating). In general, parasympathetic stimulation is believed to increase the release of insulin, glucagon, somatostatin and pancreatic polypeptide in many different species (for review, see [10, 11, 14, 15]).

Sensory nerves are also involved in the regulation of hormone secretion by endocrine cells [11]. Following chemical destruction of sensory nerves (capsaicin treatment) in mice, there is an increase in insulin secretion in response to glucose compared to control [81].

In conclusion, it should be added that pancreatic innervation is insufficiently studied, especially in humans [40, 44]. Interestingly, the innervation of the islets is very plastic: it has been shown that islets transplanted into the portal vein of diabetic rats were reinnervated by the nerves of the liver [82]. This makes it necessary to further study the role of innervation in the regulation of glucose homeostasis and plasticity of the endocrine part of the pancreas.

### **4. Pancreatic innervation during prenatal development**

Despite the clinical importance, data concerning pancreatic innervation during human ontogeny and in diseases are very limited [37]. Such studies have been performed on rodents and mostly concern the sympathetic innervation [43, 55, 83]. The embryonic sources of neural elements are fibres of the vagus (*n. vagus*) and splanchnic nerves (*n. splanchnicus*) growing into the developing pancreas and neurons that differentiate from the neural crest cells migrating to the pancreas. Sympathetic fibres innervate the developing mouse pancreas starting from the 15th day of embryonic development (E14.5) [43]. Consequently, the degree of sympathetic innervation increases until 20 days of postnatal development (P20) [55]. The development of the pancreatic sympathetic innervation depends on nerve growth factor (NGF) [43].

The human pancreas receives extensive innervation, showing peculiar growth dynamics during gestation [37]. Ingrowths of nerves in the human pancreas start at 6 weeks of development. Further morphogenesis of pancreatic innervation is characterised by the increase of sources of innervation and degree of nervous element differentiation [84, 85]. Large bundles of nerve fibres and groups of poorly differentiated neurons are found in the human pancreas starting from the 8th week of development. At the end of the 9th week, the pancreas is innervated from almost all sources, characteristic of adults (celiac plexus, superior mesenteric plexus and posterior vagal trunk) [85]. In 1940, it was shown that pancreatic nerve cells migrate from the solar plexus and from ganglia located in the wall of the duodenum and along the branches of the vagus nerve (mainly right). At the same time, neuroblasts were detected in the pancreas of 20-week-old foetuses. Moreover, even in newborns pancreatic nerve cells were neuroblastic [86].

The gradual branching of the vascular and neural networks is observed in the human pancreatic development. Primitive free nerve endings are detected starting from the 12th week of development. In an immunohistochemical study of pancreatic innervation development in human foetuses, two peaks of increase in the number of structures of the nervous system in the head of the gland were revealed at the 14th and 22th weeks. In the pancreatic body and tail, the number of nerve structures increases from the 20th week [37]. By 30–32 weeks of development, the density of nerve endings is reduced compared to previous periods [85]. The innervation of pancreatic islets in humans is formed from the 14 to 15th weeks of the development. It differs from experimental mammals (rodents): the development of pancreatic islet innervation in rodents (mouse, Mongolian gerbil and golden hamster) is observed in the first weeks after birth [83, 87, 88].

fibres formed the core, while small S100-positive cells surrounded them. The ganglionic cells were NSE-positive, and the small cells surrounding them S100-positive. The bodies of ganglion neurons were immunonegative to S100, that is, the positive reaction to S100 protein was observed in satellite cells of intrapancreatic ganglia and in Schwann cells of nerve fibre bundles, while NSE was detected in neuronal bodies and processes. In addition, NSE- and chromo-

(some islets cells)

**S100 protein Chromogranin A**

staining)

12 weeks 16 weeks —

**SNAP-25 Peripherin**

25

Development of Human Pancreatic Innervation http://dx.doi.org/10.5772/intechopen.77089

14 weeks 14 weeks

The formation of the human pancreatic islets starts only at 12 weeks of development. In the pre-foetal period, only contacts between single endocrine cells or small groups and fine nerve fibres were detected, and classical NIC I and NIC II were not found. At gestational week 10 (postconception week 8), thickening of the ductal epithelial layer was found, in which endocrine cells were concentrated forming "buds" on pancreatic ducts. As development proceeds, buds containing different types of endocrine cells separate from the ducts forming small clusters or mantle-type islets. In our studies, contacts between the structures of the nervous system and epithelial cells of primitive ducts were detected in the foetal pancreas at early stages

The formation of the pancreatic lobules begins in the early foetal period, from 13 weeks. At the same time, active formation of the islets of Langerhans and innervation of the endocrine part starts (**Figure 1b**). Nervous system of the pancreas of 14–15 week foetuses becomes more branched in comparison with 10–12 weeks of development. Large bundles of nerve fibres are localised in the connective tissue of gland's capsule. Smaller nerves pass into the interlobular connective tissue separately or along the blood vessels. Nerve fibres and ganglia are first found within the lobules. At the 16th week of development, the nervous apparatus of the pancreas is presented by bundles of nerve fibres of different diameters and nerve ganglia, which are located in the interlobular connective tissue and within the lobules. The nerve fibres connecting two nerve ganglia were found in 14–15 week foetuses, i.e. the first clearly detected

Localisation of antigens in the structures of the nervous system was also similar with the pre-foetal period. In addition, the immunopositive cells for chromogranin A, SNAP-25 and peripherin were detected in the nerve fibres and ganglia starting from 14 to 15 weeks of the development (**Table 1**). SNAP-25, NCAM, NSE, peripherin and neuron-specific β-III tubulin

granin A-positive endocrine cells were first found in 12-week foetuses (**Table 1**).

**specific β-III tubulin**

12 weeks 14 weeks 14 weeks 15–16 weeks

10 weeks 10 weeks 10 weeks 12 weeks 14 weeks (weak

**Table 1.** Appearance of immunopositive reactions to neural proteins in the developing human pancreas.

of development (10–13 weeks) before the formation of islets.

**Markers NSE NCAM Neuron-**

Nerve fibres and ganglions

Endocrine cells

integration of the nervous system structures was shown.

Our study was performed on a collection of pancreatic autopsies, which allows us to explore the features of intrapancreatic innervation directly in humans using a variety of methods: classical histology; immunohistochemistry; light, fluorescent and confocal microscopy; morphoand stereometry; statistical analysis; 3D histology; and computer reconstruction. The study was performed on 50 pancreatic autopsies of foetuses from the 10th to 40th gestational week (g.w.). Foetal pancreatic autopsies were divided into four groups according to the classification of the foetal period: pre-foetal period (10–12 g.w.), early foetal period (13–20 g.w.), middle foetal period (21–28 g.w.) and late foetal period (29–40 g.w.). A panel of antibodies for nervous system proteins (chromogranin A, neuron-specific enolase (NSE), neural cell adhesion molecule (NCAM), synaptosomal-associated protein of 25 kDa (SNAP-25, peripherin, S100 protein and neuron-specific class III β-tubulin), endocrine cell hormones (insulin, glucagon and somatostatin) and epithelial cells (cytokeratin 19 (CK19)) were used in this work [89, 90]. We generated new data concerning the spatio-temporal distribution of the innervation in the human pancreas during prenatal development.

In the pre-foetal period (10–12 g.w.), large weakly branched bundles of nerve fibres and nerve ganglia were detected already at the 10th week of gestational development using antibodies to NSE, NCAM and neuron-specific β-III tubulin (**Table 1**). The largest bundles of nerve fibres were detected in the dense peri-pancreatic mesenchyme, and the group of neurons and bundles of nerve fibres of smaller diameter were located in the loose mesenchyme between pancreatic ducts (**Figure 1a**). A network of fine nerve fibres was not developed. In some cases, bundles of nerve fibres were found near large vessels. Nerve ganglia in the pancreas of 10–12 week foetuses were small groups of cells.

Starting from 12 weeks, cells immunopositive for antibodies to S100 protein were found in nervous system structures. Localisation of neuromarkers was different. In the nerves, NSE-positive


**Table 1.** Appearance of immunopositive reactions to neural proteins in the developing human pancreas.

starting from the 8th week of development. At the end of the 9th week, the pancreas is innervated from almost all sources, characteristic of adults (celiac plexus, superior mesenteric plexus and posterior vagal trunk) [85]. In 1940, it was shown that pancreatic nerve cells migrate from the solar plexus and from ganglia located in the wall of the duodenum and along the branches of the vagus nerve (mainly right). At the same time, neuroblasts were detected in the pancreas of 20-week-old foetuses. Moreover, even in newborns pancreatic

The gradual branching of the vascular and neural networks is observed in the human pancreatic development. Primitive free nerve endings are detected starting from the 12th week of development. In an immunohistochemical study of pancreatic innervation development in human foetuses, two peaks of increase in the number of structures of the nervous system in the head of the gland were revealed at the 14th and 22th weeks. In the pancreatic body and tail, the number of nerve structures increases from the 20th week [37]. By 30–32 weeks of development, the density of nerve endings is reduced compared to previous periods [85]. The innervation of pancreatic islets in humans is formed from the 14 to 15th weeks of the development. It differs from experimental mammals (rodents): the development of pancreatic islet innervation in rodents (mouse, Mongolian gerbil and golden hamster) is observed in the first

Our study was performed on a collection of pancreatic autopsies, which allows us to explore the features of intrapancreatic innervation directly in humans using a variety of methods: classical histology; immunohistochemistry; light, fluorescent and confocal microscopy; morphoand stereometry; statistical analysis; 3D histology; and computer reconstruction. The study was performed on 50 pancreatic autopsies of foetuses from the 10th to 40th gestational week (g.w.). Foetal pancreatic autopsies were divided into four groups according to the classification of the foetal period: pre-foetal period (10–12 g.w.), early foetal period (13–20 g.w.), middle foetal period (21–28 g.w.) and late foetal period (29–40 g.w.). A panel of antibodies for nervous system proteins (chromogranin A, neuron-specific enolase (NSE), neural cell adhesion molecule (NCAM), synaptosomal-associated protein of 25 kDa (SNAP-25, peripherin, S100 protein and neuron-specific class III β-tubulin), endocrine cell hormones (insulin, glucagon and somatostatin) and epithelial cells (cytokeratin 19 (CK19)) were used in this work [89, 90]. We generated new data concerning the spatio-temporal distribution of the innervation in the

In the pre-foetal period (10–12 g.w.), large weakly branched bundles of nerve fibres and nerve ganglia were detected already at the 10th week of gestational development using antibodies to NSE, NCAM and neuron-specific β-III tubulin (**Table 1**). The largest bundles of nerve fibres were detected in the dense peri-pancreatic mesenchyme, and the group of neurons and bundles of nerve fibres of smaller diameter were located in the loose mesenchyme between pancreatic ducts (**Figure 1a**). A network of fine nerve fibres was not developed. In some cases, bundles of nerve fibres were found near large vessels. Nerve ganglia in the pancreas of

Starting from 12 weeks, cells immunopositive for antibodies to S100 protein were found in nervous system structures. Localisation of neuromarkers was different. In the nerves, NSE-positive

nerve cells were neuroblastic [86].

24 Autonomic Nervous System

weeks after birth [83, 87, 88].

human pancreas during prenatal development.

10–12 week foetuses were small groups of cells.

fibres formed the core, while small S100-positive cells surrounded them. The ganglionic cells were NSE-positive, and the small cells surrounding them S100-positive. The bodies of ganglion neurons were immunonegative to S100, that is, the positive reaction to S100 protein was observed in satellite cells of intrapancreatic ganglia and in Schwann cells of nerve fibre bundles, while NSE was detected in neuronal bodies and processes. In addition, NSE- and chromogranin A-positive endocrine cells were first found in 12-week foetuses (**Table 1**).

The formation of the human pancreatic islets starts only at 12 weeks of development. In the pre-foetal period, only contacts between single endocrine cells or small groups and fine nerve fibres were detected, and classical NIC I and NIC II were not found. At gestational week 10 (postconception week 8), thickening of the ductal epithelial layer was found, in which endocrine cells were concentrated forming "buds" on pancreatic ducts. As development proceeds, buds containing different types of endocrine cells separate from the ducts forming small clusters or mantle-type islets. In our studies, contacts between the structures of the nervous system and epithelial cells of primitive ducts were detected in the foetal pancreas at early stages of development (10–13 weeks) before the formation of islets.

The formation of the pancreatic lobules begins in the early foetal period, from 13 weeks. At the same time, active formation of the islets of Langerhans and innervation of the endocrine part starts (**Figure 1b**). Nervous system of the pancreas of 14–15 week foetuses becomes more branched in comparison with 10–12 weeks of development. Large bundles of nerve fibres are localised in the connective tissue of gland's capsule. Smaller nerves pass into the interlobular connective tissue separately or along the blood vessels. Nerve fibres and ganglia are first found within the lobules. At the 16th week of development, the nervous apparatus of the pancreas is presented by bundles of nerve fibres of different diameters and nerve ganglia, which are located in the interlobular connective tissue and within the lobules. The nerve fibres connecting two nerve ganglia were found in 14–15 week foetuses, i.e. the first clearly detected integration of the nervous system structures was shown.

Localisation of antigens in the structures of the nervous system was also similar with the pre-foetal period. In addition, the immunopositive cells for chromogranin A, SNAP-25 and peripherin were detected in the nerve fibres and ganglia starting from 14 to 15 weeks of the development (**Table 1**). SNAP-25, NCAM, NSE, peripherin and neuron-specific β-III tubulin

while SNAP-25-positive endocrine cells were detected only from 16 weeks of development. Immunopositivity to antibodies against S100 protein was found only in some islet cells start-

Development of Human Pancreatic Innervation http://dx.doi.org/10.5772/intechopen.77089 27

The contacts of nerves fibres with endocrine cells were detected starting from 12 weeks of development. Already in the early foetal period, it was possible to identify NIC I (single insulin- or glucagon-containing cells in ganglia (Supplementary Video 1) or ganglia associated with the islets) and NIC II (single endocrine cells in the nerve (Supplementary Video 2), nerve endings associated with single endocrine cells or with the islets) and make their 3D reconstruction. The analysis of three-dimensional reconstructions allowed us to show ganglia associated with two islets at once, islets associated simultaneously with two ganglia, and NIC of mixed (intermediate) type [91]. Moreover, in the foetal pancreas, starting from 13 weeks, we showed simultaneously neuro-insular complexes and contacts between the structures of nervous system and epithelial cells located in ducts as well as in cell clusters that were often connected with the ducts. Based on these findings, we suggested that the development of neuro-insular complexes may be due to integration between the structures of the nervous system and epithelial progenitors at the initial stages of islet formation. Furthermore, endocrine cells are supposed to migrate along nerve fibres from the ducts, small clusters of endocrine cells and islets to the other islets, which are located a distance from pancreatic ducts, due to exocrine pancreatic growth, thus increasing their pool of endocrine cells. We suppose that the mechanism of

pancreatic islet formation is similar to the formation of some peripheral analysers.

The pattern of immunoreactivity of neural markers during the middle (21–28 g.w.) and late foetal periods is similar to those in the early foetal period. In the middle of the foetal period, the density of pancreatic innervation is higher than in the early foetal period (**Figure 1c**, **d**). Despite increasing the size of pancreatic lobules and more sparse distribution of large and medium bundles of nerve fibres, the network of fine nerve fibres gradually branch and become denser. However, during late foetal and neonatal development, this network is much sparser (**Figure 1e**). This is due to the increase in the size of lobules. However, at all stages of human prenatal development, density of distribution of the nervous system structures is higher than in adults (**Figure 1f**). The density of NIC distribution also gradually decreases at birth. Our quantitative data indicate that the largest number of NIC I was observed in the early and middle foetal periods, during the active morphogenesis of pancreatic islets, whereas at birth (in the late foetal period) and in the adult, NIC II became more prevalent [91]. During the middle and late foetal periods, the nervous system components also contact epithelial cells located in ducts or in clusters outside the ductal epithelium and form complexes with separate epithelial cells. We observed CK19-positive cells inside the ganglia and nerve bundles, which were located separately or integrated

In this study, our previous data were confirmed and refined [89] that the formation of the nervous system in the development of human pancreas can be divided into three stages. In the pre-foetal period, the nervous apparatus of the pancreas is represented by slightly branched bundles of nerve fibres and nerve ganglia. However, the structures of the nervous system differ from the late foetuses and adults by antigenic composition. Expression of various neural

proteins does not begin simultaneously in the foetal pancreas.

ing from 15 to 16 weeks of development (**Table 1**).

within the islets [90].

**Figure 1.** Spatio-temporal distribution of the nervous system structures in the human pancreas during ontogenesis. (a, b, d–f) double immunohistochemistry on the pancreatic slices of foetuses ((a) 12 g.w., (b) 16 g.w., (d) 28 g.w.), child ((e) 3 months) and adult ((f) 88 years): (a, b) insulin (blue) + S100 (red), (d, e) insulin (red)+ NSE (blue) and (f) glucagon (red) + NSE (blue). Arrows indicate some ganglia. (c) Stack of serial immunofluorescence images of NIC in the foetal pancreas (20 g.w.) (sum thickness of slices 90 mkm): Glucagon (green) + S100 (red).

were detected in bundles of nerve fibres of different diameters and the bodies of neurons in human foetuses. However, there were fine nerve fibres located in the acinar parenchyma that were immunonegative for peripherin but reacted with other markers in all investigated cases. This suggests that nerve fibres of the human pancreas differ according to the set of expressed proteins. In addition, positive immunostaining for NCAM and neuron-specific β-III tubulin was observed in endocrine cells starting from 14 weeks of development, while SNAP-25-positive endocrine cells were detected only from 16 weeks of development. Immunopositivity to antibodies against S100 protein was found only in some islet cells starting from 15 to 16 weeks of development (**Table 1**).

The contacts of nerves fibres with endocrine cells were detected starting from 12 weeks of development. Already in the early foetal period, it was possible to identify NIC I (single insulin- or glucagon-containing cells in ganglia (Supplementary Video 1) or ganglia associated with the islets) and NIC II (single endocrine cells in the nerve (Supplementary Video 2), nerve endings associated with single endocrine cells or with the islets) and make their 3D reconstruction. The analysis of three-dimensional reconstructions allowed us to show ganglia associated with two islets at once, islets associated simultaneously with two ganglia, and NIC of mixed (intermediate) type [91]. Moreover, in the foetal pancreas, starting from 13 weeks, we showed simultaneously neuro-insular complexes and contacts between the structures of nervous system and epithelial cells located in ducts as well as in cell clusters that were often connected with the ducts. Based on these findings, we suggested that the development of neuro-insular complexes may be due to integration between the structures of the nervous system and epithelial progenitors at the initial stages of islet formation. Furthermore, endocrine cells are supposed to migrate along nerve fibres from the ducts, small clusters of endocrine cells and islets to the other islets, which are located a distance from pancreatic ducts, due to exocrine pancreatic growth, thus increasing their pool of endocrine cells. We suppose that the mechanism of pancreatic islet formation is similar to the formation of some peripheral analysers.

The pattern of immunoreactivity of neural markers during the middle (21–28 g.w.) and late foetal periods is similar to those in the early foetal period. In the middle of the foetal period, the density of pancreatic innervation is higher than in the early foetal period (**Figure 1c**, **d**). Despite increasing the size of pancreatic lobules and more sparse distribution of large and medium bundles of nerve fibres, the network of fine nerve fibres gradually branch and become denser. However, during late foetal and neonatal development, this network is much sparser (**Figure 1e**). This is due to the increase in the size of lobules. However, at all stages of human prenatal development, density of distribution of the nervous system structures is higher than in adults (**Figure 1f**). The density of NIC distribution also gradually decreases at birth. Our quantitative data indicate that the largest number of NIC I was observed in the early and middle foetal periods, during the active morphogenesis of pancreatic islets, whereas at birth (in the late foetal period) and in the adult, NIC II became more prevalent [91]. During the middle and late foetal periods, the nervous system components also contact epithelial cells located in ducts or in clusters outside the ductal epithelium and form complexes with separate epithelial cells. We observed CK19-positive cells inside the ganglia and nerve bundles, which were located separately or integrated within the islets [90].

In this study, our previous data were confirmed and refined [89] that the formation of the nervous system in the development of human pancreas can be divided into three stages. In the pre-foetal period, the nervous apparatus of the pancreas is represented by slightly branched bundles of nerve fibres and nerve ganglia. However, the structures of the nervous system differ from the late foetuses and adults by antigenic composition. Expression of various neural proteins does not begin simultaneously in the foetal pancreas.

were detected in bundles of nerve fibres of different diameters and the bodies of neurons in human foetuses. However, there were fine nerve fibres located in the acinar parenchyma that were immunonegative for peripherin but reacted with other markers in all investigated cases. This suggests that nerve fibres of the human pancreas differ according to the set of expressed proteins. In addition, positive immunostaining for NCAM and neuron-specific β-III tubulin was observed in endocrine cells starting from 14 weeks of development,

the foetal pancreas (20 g.w.) (sum thickness of slices 90 mkm): Glucagon (green) + S100 (red).

26 Autonomic Nervous System

**Figure 1.** Spatio-temporal distribution of the nervous system structures in the human pancreas during ontogenesis. (a, b, d–f) double immunohistochemistry on the pancreatic slices of foetuses ((a) 12 g.w., (b) 16 g.w., (d) 28 g.w.), child ((e) 3 months) and adult ((f) 88 years): (a, b) insulin (blue) + S100 (red), (d, e) insulin (red)+ NSE (blue) and (f) glucagon (red) + NSE (blue). Arrows indicate some ganglia. (c) Stack of serial immunofluorescence images of NIC in The second stage of development of the nervous apparatus of the pancreas (during the early and middle foetal periods) is characterised by gradual branching of the neural network and formation of connections between the structures of the nervous system and exocrine and endocrine parts. In the early foetal period, nerve fibres gradually branch, nerve fibres and nerve ganglia appear localised between the acini, and a network of fine nerve fibres starts to form. In the later stages of development, the distribution of neural structures (nerve fibres, nerve ganglia and parenchymal network of fine nerve fibres) become sparser with increase in the size of the pancreas. Thus, innervation of the pancreas at this stage of development gradually becomes similar to the distribution structures of the nervous system in the adult pancreas.

**Conflict of interest**

**Author details**

Sergey V. Saveliev1

**References**

Alexandra E. Proshchina1

The authors declare no competing interests.

\*, Yuliya S. Krivova1

\*Address all correspondence to: proshchina@yandex.ru

2013;**52**(1):R35-R49. DOI: 10.1530/JME-13-0122

3002. DOI: 10.2337/diabetes.51.10.2997

10.1016/j.cell.2006.10.038

205. DOI: 10.1038/nm818

annals.1447.0330

1 Research Institute of Human Morphology, Moscow, Russia

, Olga G. Leonova2

2 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

[1] Veld In't P, Marichal M. Microscopic anatomy of the human islet of Langerhans. In: Islam MS, editor. The Islets of Langerhans. Netherlands: Springer; 2010. pp. 1-19

[2] Wierup N, Sundler F, Heller RS.The islet ghrelin cell. Journal of Molecular Endocrinology.

[3] Lindsay TH, Halvorson KG, Peters CM, Ghilardi JR, Kuskowsk MA, Wong GY, et al. A quantitative analysis of the sensory and sympathetic innervation of the mouse pancreas.

[4] Mei Q, Mundinger TO, Lernmark A, Taborsky GJ Jr. Early, selective, and marked loss of sympathetic nerves from the islets of BioBreeder diabetic rats. Diabetes. 2002;**51**(10):2997-

[5] Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J, Tsui H, Tang L, Tsai S, Santamaria P, Driver JP, Serreze D, Salter MW, Dosch HM. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell. 2006;**127**(6):1123-1135. DOI:

[6] Tsui H, Winer S, Chan Y, Truong D, Tang L, Yantha J, et al. Islet glia, neurons, and beta cells. Annals of the New York Academy of Sciences. 2008;**1150**(1):32-42. DOI: 10.1196/

[7] Winer S, Tsui H, Lau A, Song A, Li X, Cheung RK, et al. Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. Nature Medicine. 2003;**9**(2):198-

Neuroscience. 2006;**137**(4):1417-1426. DOI: 10.1016/j.neuroscience.2005.10.055

, Valeriy M. Barabanov1

Development of Human Pancreatic Innervation http://dx.doi.org/10.5772/intechopen.77089

and

29

In our studies, we demonstrated close integration between the structures of the nervous system and endocrine cells in the human pancreas, which were more frequently observed during prenatal development. Thus, a dense network is formed in the developing human pancreas, in which the structures of the nervous system are associated with the islets of Langerhans. The close relationship between developing islets and structures of the nervous system suggests that neuroendocrine interactions can influence not only the secretion of hormones but also to participate in the morphogenesis of the islets, presumably due to the participation in migration of endocrine cells from ducts to islets. Understanding the role of NICs in islet formation can lead to new approaches to understanding the mechanisms and treatment of diabetes.

#### **5. Conclusions**

Thus, our knowledge about the peripheral nervous system in the human pancreas is limited. Importantly, human islet development has not been examined for the presence of classical markers of the parasympathetic and sympathetic nervous systems. Furthermore, the exact location where neuronal axons terminate within the human islets in adults was not shown until recently.

However, the human pancreas is abundantly innervated during the gestational period. The value of such an abundant innervation of the pancreas and pancreatic islets, in particular, in human development is not clear. The observed differences between the nervous apparatus of foetuses and adults may have functional significance for pancreatic morphogenesis. Interestingly, some authors have described similar dynamics of innervation development in other internal human organs. The close relationship between the nervous and endocrine systems makes it necessary to further study the role of innervation in the plasticity of the endocrine pancreas both during formation of endocrine function and disorders of carbohydrate metabolism.

#### **Acknowledgements**

This work was supported by the Russian Foundation for Basic Research, project no. 18-015- 00146.

### **Conflict of interest**

The second stage of development of the nervous apparatus of the pancreas (during the early and middle foetal periods) is characterised by gradual branching of the neural network and formation of connections between the structures of the nervous system and exocrine and endocrine parts. In the early foetal period, nerve fibres gradually branch, nerve fibres and nerve ganglia appear localised between the acini, and a network of fine nerve fibres starts to form. In the later stages of development, the distribution of neural structures (nerve fibres, nerve ganglia and parenchymal network of fine nerve fibres) become sparser with increase in the size of the pancreas. Thus, innervation of the pancreas at this stage of development gradually becomes similar to the distribution structures of the nervous system in the adult pancreas. In our studies, we demonstrated close integration between the structures of the nervous system and endocrine cells in the human pancreas, which were more frequently observed during prenatal development. Thus, a dense network is formed in the developing human pancreas, in which the structures of the nervous system are associated with the islets of Langerhans. The close relationship between developing islets and structures of the nervous system suggests that neuroendocrine interactions can influence not only the secretion of hormones but also to participate in the morphogenesis of the islets, presumably due to the participation in migration of endocrine cells from ducts to islets. Understanding the role of NICs in islet formation can lead to new approaches to understanding the mechanisms and treatment of diabetes.

Thus, our knowledge about the peripheral nervous system in the human pancreas is limited. Importantly, human islet development has not been examined for the presence of classical markers of the parasympathetic and sympathetic nervous systems. Furthermore, the exact location where neuronal axons terminate within the human islets in adults was not shown

However, the human pancreas is abundantly innervated during the gestational period. The value of such an abundant innervation of the pancreas and pancreatic islets, in particular, in human development is not clear. The observed differences between the nervous apparatus of foetuses and adults may have functional significance for pancreatic morphogenesis. Interestingly, some authors have described similar dynamics of innervation development in other internal human organs. The close relationship between the nervous and endocrine systems makes it necessary to further study the role of innervation in the plasticity of the endocrine pancreas both during

This work was supported by the Russian Foundation for Basic Research, project no. 18-015-

formation of endocrine function and disorders of carbohydrate metabolism.

**5. Conclusions**

28 Autonomic Nervous System

until recently.

**Acknowledgements**

00146.

The authors declare no competing interests.

#### **Author details**

Alexandra E. Proshchina1 \*, Yuliya S. Krivova1 , Olga G. Leonova2 , Valeriy M. Barabanov1 and Sergey V. Saveliev1

\*Address all correspondence to: proshchina@yandex.ru


#### **References**


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[30] Von Dorsche HH, Falt K, Hahn HJ, Reiher H. Neuron-specific enolase (NSE) as a neuroendocrine cell marker in the human fetal pancreas. Acta Histochemica. 1989;**85**(2):227-

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**Section 3**

**Autonomic Nervous System and Implications in**

**Clinical Practice**

**Autonomic Nervous System and Implications in Clinical Practice**

**Chapter 3**

**Provisional chapter**

**Autonomic Nervous System and Neurocardiac**

John G. Kingma, Denys Simard and Jacques R. Rouleau

**Autonomic Nervous System and Neurocardiac** 

DOI: 10.5772/intechopen.77087

The autonomic nervous system regulates multiple physiological functions; how distinct neurons in peripheral autonomic and intrathoracic ganglia communicate remains to be established. Increasing focus is being paid to functionality of the neurocardiac axis and crosstalk between the intrinsic nervous system and diverse organ systems. Current findings indicate that progression of cardiovascular disease comprises peripheral and central aspects of the cardiac nervous system hierarchy. Indeed, autonomic neuronal dysfunction is known to participate in arrhythmogenesis and sudden cardiac death; diverse interventions (pharmacological, non-pharmacological) that affect neuronal remodeling in the heart following injury caused by cardiovascular disease (congestive heart failure, etc.) or acute myocardial infarction are being investigated. Herein we examine recent findings from clinical and animal studies on the role of the intrinsic cardiac nervous system on regulation of myocardial perfusion and the consequences of cardiac injury. We also discuss different interventions that target the autonomic nervous system, stimulate

neuronal remodeling and adaptation, and thereby optimize patient outcomes.

cardiac neurons, intrinsic cardiac nervous system, ischemia, arrhythmias

**Keywords:** autonomic nervous system, sympathetic, parasympathetic nerves, intrinsic

Physiological functions (i.e. muscle contraction, glandular function, visceral activity, nerve impulses, etc.) of the body are controlled by the autonomic nervous system (ANS). Innervation to the heart is consistent among species [1–3]; the ANS comprises central, intrathoracic extracardiac and intrinsic cardiac components (see review by Hanna et al. [4]). The sympathetic and parasympathetic systems interact to stimulate energy expenditure under conditions of stress or return the

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Physiopathology**

**Physiopathology**

Jacques R. Rouleau

**Abstract**

**1. Introduction**

John G. Kingma, Denys Simard and

http://dx.doi.org/10.5772/intechopen.77087

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Autonomic Nervous System and Neurocardiac Physiopathology Autonomic Nervous System and Neurocardiac Physiopathology**

DOI: 10.5772/intechopen.77087

John G. Kingma, Denys Simard and Jacques R. Rouleau John G. Kingma, Denys Simard and Jacques R. Rouleau Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77087

#### **Abstract**

The autonomic nervous system regulates multiple physiological functions; how distinct neurons in peripheral autonomic and intrathoracic ganglia communicate remains to be established. Increasing focus is being paid to functionality of the neurocardiac axis and crosstalk between the intrinsic nervous system and diverse organ systems. Current findings indicate that progression of cardiovascular disease comprises peripheral and central aspects of the cardiac nervous system hierarchy. Indeed, autonomic neuronal dysfunction is known to participate in arrhythmogenesis and sudden cardiac death; diverse interventions (pharmacological, non-pharmacological) that affect neuronal remodeling in the heart following injury caused by cardiovascular disease (congestive heart failure, etc.) or acute myocardial infarction are being investigated. Herein we examine recent findings from clinical and animal studies on the role of the intrinsic cardiac nervous system on regulation of myocardial perfusion and the consequences of cardiac injury. We also discuss different interventions that target the autonomic nervous system, stimulate neuronal remodeling and adaptation, and thereby optimize patient outcomes.

**Keywords:** autonomic nervous system, sympathetic, parasympathetic nerves, intrinsic cardiac neurons, intrinsic cardiac nervous system, ischemia, arrhythmias

#### **1. Introduction**

Physiological functions (i.e. muscle contraction, glandular function, visceral activity, nerve impulses, etc.) of the body are controlled by the autonomic nervous system (ANS). Innervation to the heart is consistent among species [1–3]; the ANS comprises central, intrathoracic extracardiac and intrinsic cardiac components (see review by Hanna et al. [4]). The sympathetic and parasympathetic systems interact to stimulate energy expenditure under conditions of stress or return the

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

body to a restful state; these systems comprise pathways that include preganglionic and postganglionic neurons (activated by endogenous chemical neurotransmitters). Increasing attention focuses on the complex anatomy and function of the cardiac neuraxis; how diverse populations of neurons in peripheral autonomic and intrathoracic ganglia communicate with each other and between different organ systems remains the subject of ongoing investigation. Treatment strategies that modulate the ANS are being developed and tested in the setting of cardiac dysfunction, arrhythmias and sudden death with the objective of stimulating or maintaining cardiovascular function. Improved mechanistic understanding of changes that occur within the nervous system hierarchy during pathogenesis of cardiac disease is therefore essential. This chapter examines current scientific literature on the effects of ischemia on the cardiac nervous system; the role of intrinsic cardiac neurons on regulation of myocardial blood flow, cardiac function, pathogenesis of nerve and myocardial tissue injury is discussed. For this review, clinical and basic science reports were searched on MEDLINE, Google Scholar and PubMed with the keywords intrinsic cardiac nervous system (ICNS), ischemia, reperfusion, cellular protection, myocardium, nerves and combinations thereof. In addition, we referred to data from our own research.

**3. Vasoregulation**

Arteries normally respond to humoral, metabolic, mechanical and neural stimulation; local metabolic control occurs secondarily to myocardial metabolic change [34, 35]. In the heart, blood flow across the ventricular wall is precisely coordinated to metabolic requirements via adjustments in vessel tone; flow is therefore independent of external physical factors since metabolism is the ultimate determinant of regional perfusion over the operative range of autoregulation [36–38]. The ANS contributes to regulation of myocardial blood flow; sympathetic nerve stimulation produces a biphasic response, which trends to coronary dilatation resulting from increases in myocardial oxygen demand as well as perfusion pressure [39, 40]. Neuropeptide chemicals elevate local catecholamine levels that modulate cardiac dynamics and indirectly increase blood flow across the left ventricular wall [40–42]. In dogs, with an intact cardiac nervous system, we documented significant increases in myocardial blood flow following application of nicotine or bradykinin to selected ganglionated plexi on the heart [40]; stimulation of nicotine sensitive neurons increases cardiac metabolic demand (i.e. higher heart rate and LV systolic pressure) but stimulation with bradykinin produces a similar result without affecting LV pressure. On the other hand, Vergroesen et al. documented that intact cardiac nerves were not essential for regulation of coronary blood flow [43]; however, they suggested that cardiac nerves essentially alter the speed of response of the coronary vascular bed to changes in heart rate and perfusion pressure. The cardiac nervous reflexes thought to be responsible for these effects has not been established but diverse cardiac afferent fibers and

Autonomic Nervous System and Neurocardiac Physiopathology

http://dx.doi.org/10.5772/intechopen.77087

41

receptor subtypes (i.e. ventricular, coronary artery) have been studied.

progression of coronary artery disease.

Stimulation of ventricular mechanoreceptors causes an increase in arterial perfusion pressure, which results in greater blood volume and reflex coronary vasodilatation [44, 45]; higher perfusion pressures promote vasoconstriction. However, stimulation of coronary artery baroreceptors also promote reflex vasodilatation [46]. These reflex responses following mechanoreceptor stimulation may confer protection against arterial injury and thereby slow

Local release of prostaglandins, nitric oxide (NO) and endothelium-derived relaxation factors stimulate activation of select populations of cardiac neurons that contribute to vasoregulation. NO contributes to neuronal mediated vasoregulation; NO induced vasodilatation involves adrenergic, myogenic and hormonal influences [47, 48]. NO in concert with other vasoactive mediators effectively counteracts vasoconstrictor mechanisms [49–51]; these effects may be gender dependent. Three nitric oxide synthase (NOS) isoforms that synthesize NO from l-arginine have been documented; of these, two are constitutively expressed Ca2+-dependent isoforms eNOS (endothelial) is localized in cardiocytes as well as vascular and endocardial endothelium while nNOS (neuronal) is found in cardiac neurons [52–54]. The ubiquitous nature of NO implies a role in regulation of central nervous system, myocardium and vascular function [55]; nNOS and cardiac inhibitory G protein are believed to work in parallel in order to reduce sinus node rate and thereby modulate heart rate variability [56]. NO directly affects intrinsic cardiac neurons; almost 40% of these neurons are NOS positive [57]. Altered neuronal effects of NO

may be important in pathogenesis of hypertension, septic shock, diabetes mellitus, etc.

#### **2. Cardiac nervous system**

The sympathetic (adrenergic) component of the ANS stimulates cardiac conduction and myocardial cells; on the other hand, the parasympathetic (cholinergic) nervous system exerts an inhibitory influence [5, 6]. Regulation of cardiac performance by the ANS involves modulation of heart rate (positive chronotropy), increases in cardiac contractility (positive inotropy) and cardiac relaxation (positive lusitropy), decreased venous capacitance plus constriction of resistance and cutaneous vessels [7].

Sympathetic cardiac nerves originate from stellate, superior, middle cervical and thoracic ganglia [8]; postganglionic sympathetic neurons project efferent axons to the heart [9]. Parasympathetic nerves develop from the cardiac component of the cranial neural crest; preganglionic neurons access to the heart occurs via the vagus nerves [10, 11]. Cardiac ganglia are located in epicardial fat, in ganglionated plexi adjacent to the major cardiac vessels and in the ventricular wall [12–14]. ANS neurons are classified by chemical phenotyping; cholinergic and adrenergic populations of ganglionic cardiac neurons are readily found in cardiac ganglia [15–17]. Sensory neurons, interneurons and sensory fibers that develop from the *nucleus ambiguus* [18–20] likely play a role in pathogenesis of cardiac disease. In fact, activation of the neuroendocrine system is considered central to pathogenesis of cardiac disease; excess sympathetic activation promotes cardiovascular dysfunction, arrhythmias and sudden death [21]. Of note, is that visualization of the ICNS and the presence of interneuron connections is particularly challenging [22–25]; however, several immune histochemical techniques which target specific neurotransmitters within parasympathetic and sympathetic neurons have been particularly successful [26–30]. Neuroimaging techniques, cardioneural optical mapping and optogenetics are also being used to define the complex anatomy of the cardiac nervous system in animals and living humans to evaluate the role of the ANS in normal cardiac function as well as pathogenesis of cardiac disease [4, 31–33].

#### **3. Vasoregulation**

body to a restful state; these systems comprise pathways that include preganglionic and postganglionic neurons (activated by endogenous chemical neurotransmitters). Increasing attention focuses on the complex anatomy and function of the cardiac neuraxis; how diverse populations of neurons in peripheral autonomic and intrathoracic ganglia communicate with each other and between different organ systems remains the subject of ongoing investigation. Treatment strategies that modulate the ANS are being developed and tested in the setting of cardiac dysfunction, arrhythmias and sudden death with the objective of stimulating or maintaining cardiovascular function. Improved mechanistic understanding of changes that occur within the nervous system hierarchy during pathogenesis of cardiac disease is therefore essential. This chapter examines current scientific literature on the effects of ischemia on the cardiac nervous system; the role of intrinsic cardiac neurons on regulation of myocardial blood flow, cardiac function, pathogenesis of nerve and myocardial tissue injury is discussed. For this review, clinical and basic science reports were searched on MEDLINE, Google Scholar and PubMed with the keywords intrinsic cardiac nervous system (ICNS), ischemia, reperfusion, cellular protection, myocardium, nerves

and combinations thereof. In addition, we referred to data from our own research.

The sympathetic (adrenergic) component of the ANS stimulates cardiac conduction and myocardial cells; on the other hand, the parasympathetic (cholinergic) nervous system exerts an inhibitory influence [5, 6]. Regulation of cardiac performance by the ANS involves modulation of heart rate (positive chronotropy), increases in cardiac contractility (positive inotropy) and cardiac relaxation (positive lusitropy), decreased venous capacitance plus constriction of

Sympathetic cardiac nerves originate from stellate, superior, middle cervical and thoracic ganglia [8]; postganglionic sympathetic neurons project efferent axons to the heart [9]. Parasympathetic nerves develop from the cardiac component of the cranial neural crest; preganglionic neurons access to the heart occurs via the vagus nerves [10, 11]. Cardiac ganglia are located in epicardial fat, in ganglionated plexi adjacent to the major cardiac vessels and in the ventricular wall [12–14]. ANS neurons are classified by chemical phenotyping; cholinergic and adrenergic populations of ganglionic cardiac neurons are readily found in cardiac ganglia [15–17]. Sensory neurons, interneurons and sensory fibers that develop from the *nucleus ambiguus* [18–20] likely play a role in pathogenesis of cardiac disease. In fact, activation of the neuroendocrine system is considered central to pathogenesis of cardiac disease; excess sympathetic activation promotes cardiovascular dysfunction, arrhythmias and sudden death [21]. Of note, is that visualization of the ICNS and the presence of interneuron connections is particularly challenging [22–25]; however, several immune histochemical techniques which target specific neurotransmitters within parasympathetic and sympathetic neurons have been particularly successful [26–30]. Neuroimaging techniques, cardioneural optical mapping and optogenetics are also being used to define the complex anatomy of the cardiac nervous system in animals and living humans to evaluate the role of the ANS in normal cardiac function as

**2. Cardiac nervous system**

40 Autonomic Nervous System

resistance and cutaneous vessels [7].

well as pathogenesis of cardiac disease [4, 31–33].

Arteries normally respond to humoral, metabolic, mechanical and neural stimulation; local metabolic control occurs secondarily to myocardial metabolic change [34, 35]. In the heart, blood flow across the ventricular wall is precisely coordinated to metabolic requirements via adjustments in vessel tone; flow is therefore independent of external physical factors since metabolism is the ultimate determinant of regional perfusion over the operative range of autoregulation [36–38]. The ANS contributes to regulation of myocardial blood flow; sympathetic nerve stimulation produces a biphasic response, which trends to coronary dilatation resulting from increases in myocardial oxygen demand as well as perfusion pressure [39, 40]. Neuropeptide chemicals elevate local catecholamine levels that modulate cardiac dynamics and indirectly increase blood flow across the left ventricular wall [40–42]. In dogs, with an intact cardiac nervous system, we documented significant increases in myocardial blood flow following application of nicotine or bradykinin to selected ganglionated plexi on the heart [40]; stimulation of nicotine sensitive neurons increases cardiac metabolic demand (i.e. higher heart rate and LV systolic pressure) but stimulation with bradykinin produces a similar result without affecting LV pressure. On the other hand, Vergroesen et al. documented that intact cardiac nerves were not essential for regulation of coronary blood flow [43]; however, they suggested that cardiac nerves essentially alter the speed of response of the coronary vascular bed to changes in heart rate and perfusion pressure. The cardiac nervous reflexes thought to be responsible for these effects has not been established but diverse cardiac afferent fibers and receptor subtypes (i.e. ventricular, coronary artery) have been studied.

Stimulation of ventricular mechanoreceptors causes an increase in arterial perfusion pressure, which results in greater blood volume and reflex coronary vasodilatation [44, 45]; higher perfusion pressures promote vasoconstriction. However, stimulation of coronary artery baroreceptors also promote reflex vasodilatation [46]. These reflex responses following mechanoreceptor stimulation may confer protection against arterial injury and thereby slow progression of coronary artery disease.

Local release of prostaglandins, nitric oxide (NO) and endothelium-derived relaxation factors stimulate activation of select populations of cardiac neurons that contribute to vasoregulation. NO contributes to neuronal mediated vasoregulation; NO induced vasodilatation involves adrenergic, myogenic and hormonal influences [47, 48]. NO in concert with other vasoactive mediators effectively counteracts vasoconstrictor mechanisms [49–51]; these effects may be gender dependent. Three nitric oxide synthase (NOS) isoforms that synthesize NO from l-arginine have been documented; of these, two are constitutively expressed Ca2+-dependent isoforms eNOS (endothelial) is localized in cardiocytes as well as vascular and endocardial endothelium while nNOS (neuronal) is found in cardiac neurons [52–54]. The ubiquitous nature of NO implies a role in regulation of central nervous system, myocardium and vascular function [55]; nNOS and cardiac inhibitory G protein are believed to work in parallel in order to reduce sinus node rate and thereby modulate heart rate variability [56]. NO directly affects intrinsic cardiac neurons; almost 40% of these neurons are NOS positive [57]. Altered neuronal effects of NO may be important in pathogenesis of hypertension, septic shock, diabetes mellitus, etc.

Studies from our laboratory, in dogs subject to acute cardiac decentralization, indicated that intrinsic cardiac neurons function independently of central neuronal inputs. In decentralized and innervated hearts coronary autoregulation was similar (**Figure 1**) despite substantial reductions in myocardial oxygen demand (in decentralized hearts) [58]. In addition, perfusion across the ventricular wall (in decentralized hearts; **Figure 2**) was preserved thus confirming earlier findings of Rimoldi and coworkers [59] who reported no change in transmural distribution of myocardial blood flow after regional sympathetic denervation. Stability of perfusion across the ventricular wall was suggested to be due to several factors including neuronal modulation, autoregulation and variations in coronary resistance at the microvessel level (<100 μm). Interestingly, in neuropathy patients the innervation/ventricular perfusion ratio during reactive hyperemia is lower in innervated compared to denervated regions within the ventricular wall [60]. These findings are considerably different from those reported in human

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Ischemia significantly modulates function of intrinsic cardiac neurons because of local accumulations of metabolic by-products (i.e. reactive oxygen species, purinergic compounds, etc.) [62–64]. A limited number of animal studies have investigated the overall effects of ischemia on activity of nerves that course over, or through infarcted myocardium [65]; findings indicate that blood supply to these cardiac nerves is not a determining factor for conduction of action potentials [66]. The question of whether, or not, cardiac nerves are more, or less, sensitive to ischemia is less adequately studied; consequently, the injury threshold of cardiac nerves and neurons remains unknown. However, it is possible that activity of cardiac neurons post-ischemia is preserved consequent to stimulation of ventricular sensory neurites that transduce mechanical and chemical milieu in the myocardium [67]. During acute myocardial ischemia, norepinephrine is released from sympathetic nerves; this triggers sympathetic nerve regeneration (i.e. sprouting, budding) and nerve remodeling to promote sympathetic hyperinnervation, which ultimately plays a role in arrhythmogenesis [68–72]. Function of cardiac sympathetic neurons post-ischemia can also be triggered by the elevated production of intra-neuronal galanin (i.e. promotes regeneration of sympathetic axons) [73]; galanin modifies synaptic transmission and contributes to arrhythmogenesis and sudden cardiac death. Additionally, multiple autacoids (adenosine, bradykinin, NO, reactive oxygen species, etc.) produced during ischemia stimulate the central nervous system, cardiac autonomic ganglia and sympathetic efferent postganglionic axons in coronary vessels [74, 75]. Neuropeptide chemicals released from sensory neurites also modulate intrinsic cardiac neuronal activity [41, 76]. It is interesting to speculate that common survival pathways of cardiac neurons may

Infarction causes major changes between peripheral and central aspects of the cardiac nervous system; structural and functional alterations at the cardiomyocyte level include; (1) changes in collagen matrix [77], (2) induction of electromechanical dyssynchrony [78], (3) ventricular contractile dysfunction [79], apoptosis [80], etc. In the heart, ischemia affects the ICNS which is the convergence point for cardiac neural control. As such, afferent inputs are modulated

subjects after suppression of adenosine-mediated sympathetic activation [61].

be shared with cardiocytes but this has not been established.

**4. Ischemic injury**

**4.1. Nervous system**

**4.2. Heart**

**Figure 1.** Coronary blood flow versus diastolic coronary artery pressure during autoregulation. Pressure-flow relations in dogs with intact cardiac nerves (closed circles) and after extracardiac nerve ablation (open circles) are shown. Note the similarity between the two curves; reactive hyperemia blood flow was lower in decentralized dogs as shown.

**Figure 2.** Myocardial blood flow distribution across the ventricular wall (measured with microspheres) in hearts from dogs with intact cardiac nerves (closed symbols) and after acute cardiac decentralization (open symbols). Data are means ± SEM.

earlier findings of Rimoldi and coworkers [59] who reported no change in transmural distribution of myocardial blood flow after regional sympathetic denervation. Stability of perfusion across the ventricular wall was suggested to be due to several factors including neuronal modulation, autoregulation and variations in coronary resistance at the microvessel level (<100 μm). Interestingly, in neuropathy patients the innervation/ventricular perfusion ratio during reactive hyperemia is lower in innervated compared to denervated regions within the ventricular wall [60]. These findings are considerably different from those reported in human subjects after suppression of adenosine-mediated sympathetic activation [61].

#### **4. Ischemic injury**

#### **4.1. Nervous system**

Ischemia significantly modulates function of intrinsic cardiac neurons because of local accumulations of metabolic by-products (i.e. reactive oxygen species, purinergic compounds, etc.) [62–64]. A limited number of animal studies have investigated the overall effects of ischemia on activity of nerves that course over, or through infarcted myocardium [65]; findings indicate that blood supply to these cardiac nerves is not a determining factor for conduction of action potentials [66]. The question of whether, or not, cardiac nerves are more, or less, sensitive to ischemia is less adequately studied; consequently, the injury threshold of cardiac nerves and neurons remains unknown. However, it is possible that activity of cardiac neurons post-ischemia is preserved consequent to stimulation of ventricular sensory neurites that transduce mechanical and chemical milieu in the myocardium [67]. During acute myocardial ischemia, norepinephrine is released from sympathetic nerves; this triggers sympathetic nerve regeneration (i.e. sprouting, budding) and nerve remodeling to promote sympathetic hyperinnervation, which ultimately plays a role in arrhythmogenesis [68–72]. Function of cardiac sympathetic neurons post-ischemia can also be triggered by the elevated production of intra-neuronal galanin (i.e. promotes regeneration of sympathetic axons) [73]; galanin modifies synaptic transmission and contributes to arrhythmogenesis and sudden cardiac death. Additionally, multiple autacoids (adenosine, bradykinin, NO, reactive oxygen species, etc.) produced during ischemia stimulate the central nervous system, cardiac autonomic ganglia and sympathetic efferent postganglionic axons in coronary vessels [74, 75]. Neuropeptide chemicals released from sensory neurites also modulate intrinsic cardiac neuronal activity [41, 76]. It is interesting to speculate that common survival pathways of cardiac neurons may be shared with cardiocytes but this has not been established.

#### **4.2. Heart**

**Figure 2.** Myocardial blood flow distribution across the ventricular wall (measured with microspheres) in hearts from dogs with intact cardiac nerves (closed symbols) and after acute cardiac decentralization (open symbols). Data are means

**Figure 1.** Coronary blood flow versus diastolic coronary artery pressure during autoregulation. Pressure-flow relations in dogs with intact cardiac nerves (closed circles) and after extracardiac nerve ablation (open circles) are shown. Note the

similarity between the two curves; reactive hyperemia blood flow was lower in decentralized dogs as shown.

Studies from our laboratory, in dogs subject to acute cardiac decentralization, indicated that intrinsic cardiac neurons function independently of central neuronal inputs. In decentralized and innervated hearts coronary autoregulation was similar (**Figure 1**) despite substantial reductions in myocardial oxygen demand (in decentralized hearts) [58]. In addition, perfusion across the ventricular wall (in decentralized hearts; **Figure 2**) was preserved thus confirming

± SEM.

42 Autonomic Nervous System

Infarction causes major changes between peripheral and central aspects of the cardiac nervous system; structural and functional alterations at the cardiomyocyte level include; (1) changes in collagen matrix [77], (2) induction of electromechanical dyssynchrony [78], (3) ventricular contractile dysfunction [79], apoptosis [80], etc. In the heart, ischemia affects the ICNS which is the convergence point for cardiac neural control. As such, afferent inputs are modulated along with descending neural inputs [78] (i.e. including reflex-induced sympathoexcitation and reduced central drive from parasympathetic nerves [81, 82]). Heightened sympathetic tone partly mediated by neurotransmission through the stellate ganglia has been linked to cardiac pathogenesis as well as risk of cardiac arrhythmias and sudden death [83, 84].

Acute coronary artery occlusion produces distinct alterations in cardiomyocyte pathology that ultimately contribute to cell death; for cardiac myocytes a transmural gradient of cell death occurs in relation to duration and degree of ischemia [85, 86]. Transmural necrosis is mostly manifest by 6 h after acute coronary occlusion; the potential for tissue salvage after this time is limited (i.e. species dependent). Physiopathology of ischemic injury is generally well-documented [87–90]; numerous cytoprotective strategies to limit ischemic injury (i.e. pharmacologic, endogenous, etc.) have been tested but none has achieved widespread clinical use [90–92]. Post-ischemic remodeling of sympathetic neurons in stellate ganglia is not well established; however, a potential relation exists between ganglion inflammation and oxidative stress [93]. A recent study in rodents documented greater oxidative stress (i.e. lipofuscin accumulation, mitochondrial degeneration, etc.), metabolic activity (higher rate of lipid peroxidation) and inflammation in stellate glial cells [94]. These physiopathological mechanisms are believed to contribute to local inflammation (i.e. leukocyte infiltration) within stellate ganglia; this stimulates neuronal activity and oxidative stress, which increases cardiac afferent neurotransmission [95]. Other contributing factors include circulating neurohormonal compounds (i.e. angiotensin II, etc.) and brainstem-mediated increases in efferent sympathetic outflow [96–98]. Equally, cardiac inflammation and oxidative stress produced by repeated defibrillation are involved in ganglion pathology [99].

**4.3. Cardiac arrhythmogenesis**

hexamethonium bromide (HEX). Data are mean ± 1SD; n = 8/group.

Sudden cardiac death due to ventricular arrhythmias is highly relevant to cardiovascular disease related mortality [113]; autonomic neuronal dysfunction is a major contributor to induction of atrial and ventricular dysrhythmias [114–116]. Pathologically induced disturbances in neural processing within the cardiac neural hierarchy affect efferent neuronal outputs throughout the myocardium [19, 117] (i.e. intrinsic and extrinsic cardiac ganglia, central reflexes [95, 118–121]). Cardiac neurons are generally classified as afferent, efferent or convergent on the basis of responses to various cardiovascular stimuli [31, 120]. A study from Ardell's laboratory examined functional remodeling of neuronal elements within the context of myocardial infarction [120]; they showed that: (1) morphological and phenotypic remodeling of intracardiac ganglia is dependent on the site of injury, (2) attenuation of afferent neural signals to intrinsic cardiac neurons (i.e. within ischemic zone) but preservation of these signals in remote and border regions (i.e. neural sensory border zone), (3) autonomic efferent inputs to intrinsic cardiac neurons are maintained, (4) transduction capacity increases in convergent intrinsic local circuit neurons (of the heart) and (5) connectivity of intrinsic cardiac neurons is reduced. Current findings suggest that neuronal remodeling can occur independently of direct injury to specific neuron subsets; as such, neuronal plasticity within the cardiac neuroaxis is crucial post-infarction and during progression of cardiovascular disease [122, 123]. Indeed, healed myocardium provides a particular challenge to electrical propagation and regulation of cardiac function [124, 125]; abnormal cardiac efferent signaling results in continuous discord between central and peripheral aspects within the neural hierarchy that produces fatal arrhythmias due to excessive sympathoexcitation [122]. The peri-infarct region (i.e. interface between dense scar and surviving myocardium) also has an increased potential for ectopic beats [71, 126]. Ajijola and coworkers recently determined that (1) despite scarring, myocyte loss and ion channel remodeling significant regulation of electrical activation

**Figure 3.** Histogram of myocardial infarct size (as percent of anatomic area at risk) in dogs undergoing ischemia– reperfusion injury. Three distinct groups are shown: (1) control (CTR); (2) acute cardiac decentralized (DCN) and (3)

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The importance of cardiac nerves for the pathogenesis of post-ischemic infarct development and cardiac dysfunction has been investigated in experimental models of ischemia-reperfusion injury. In cardiac decentralized pigs, significant ventricular dysfunction accompanied by patchy subendocardial necrosis occurs after acute coronary occlusion [100]; myocardial perfusion-function relations in these animals were not affected by nerve status. In addition, we reported coronary vascular reserve to be comparable after nerve ablation albeit in a different experimental model [101], which is consistent with most published findings [102–105]. We also confirmed a trend towards smaller infarcts in dogs subject to extracardiac nerve ablation or pharmacologic decentralization using the autonomic ganglionic blocker hexamethonium bromide (**Figure 3**) [106]; these findings are also in agreement with earlier studies documenting increased tolerance to ischemic injury and a reduction in ventricular fibrillation threshold post-decentralization [102, 107, 108]. Reduced oxygen demand and improved perfusion of affected tissues could be responsible for increased ischemic tolerance of myocytes [43, 104, 105, 109] in the absence of intact cardiac nerves. Of note, extracardiac surgical ablation of sympathetic and parasympathetic efferent neuronal inputs produces a decentralized (not denervated) heart without complete elimination of parasympathetic involvement [110, 111]; on the other hand, pharmacologic ganglionic blockade with hexamethonium bromide blocks transmission within peripheral autonomic ganglia and vagal cardio-acceleration [112]. Continued research into the identification of endogenous compounds that modulate or activate intrinsic neuronal populations to induce cellular protection remains a priority.

**Figure 3.** Histogram of myocardial infarct size (as percent of anatomic area at risk) in dogs undergoing ischemia– reperfusion injury. Three distinct groups are shown: (1) control (CTR); (2) acute cardiac decentralized (DCN) and (3) hexamethonium bromide (HEX). Data are mean ± 1SD; n = 8/group.

#### **4.3. Cardiac arrhythmogenesis**

along with descending neural inputs [78] (i.e. including reflex-induced sympathoexcitation and reduced central drive from parasympathetic nerves [81, 82]). Heightened sympathetic tone partly mediated by neurotransmission through the stellate ganglia has been linked to

Acute coronary artery occlusion produces distinct alterations in cardiomyocyte pathology that ultimately contribute to cell death; for cardiac myocytes a transmural gradient of cell death occurs in relation to duration and degree of ischemia [85, 86]. Transmural necrosis is mostly manifest by 6 h after acute coronary occlusion; the potential for tissue salvage after this time is limited (i.e. species dependent). Physiopathology of ischemic injury is generally well-documented [87–90]; numerous cytoprotective strategies to limit ischemic injury (i.e. pharmacologic, endogenous, etc.) have been tested but none has achieved widespread clinical use [90–92]. Post-ischemic remodeling of sympathetic neurons in stellate ganglia is not well established; however, a potential relation exists between ganglion inflammation and oxidative stress [93]. A recent study in rodents documented greater oxidative stress (i.e. lipofuscin accumulation, mitochondrial degeneration, etc.), metabolic activity (higher rate of lipid peroxidation) and inflammation in stellate glial cells [94]. These physiopathological mechanisms are believed to contribute to local inflammation (i.e. leukocyte infiltration) within stellate ganglia; this stimulates neuronal activity and oxidative stress, which increases cardiac afferent neurotransmission [95]. Other contributing factors include circulating neurohormonal compounds (i.e. angiotensin II, etc.) and brainstem-mediated increases in efferent sympathetic outflow [96–98]. Equally, cardiac inflammation and oxidative stress produced by

The importance of cardiac nerves for the pathogenesis of post-ischemic infarct development and cardiac dysfunction has been investigated in experimental models of ischemia-reperfusion injury. In cardiac decentralized pigs, significant ventricular dysfunction accompanied by patchy subendocardial necrosis occurs after acute coronary occlusion [100]; myocardial perfusion-function relations in these animals were not affected by nerve status. In addition, we reported coronary vascular reserve to be comparable after nerve ablation albeit in a different experimental model [101], which is consistent with most published findings [102–105]. We also confirmed a trend towards smaller infarcts in dogs subject to extracardiac nerve ablation or pharmacologic decentralization using the autonomic ganglionic blocker hexamethonium bromide (**Figure 3**) [106]; these findings are also in agreement with earlier studies documenting increased tolerance to ischemic injury and a reduction in ventricular fibrillation threshold post-decentralization [102, 107, 108]. Reduced oxygen demand and improved perfusion of affected tissues could be responsible for increased ischemic tolerance of myocytes [43, 104, 105, 109] in the absence of intact cardiac nerves. Of note, extracardiac surgical ablation of sympathetic and parasympathetic efferent neuronal inputs produces a decentralized (not denervated) heart without complete elimination of parasympathetic involvement [110, 111]; on the other hand, pharmacologic ganglionic blockade with hexamethonium bromide blocks transmission within peripheral autonomic ganglia and vagal cardio-acceleration [112]. Continued research into the identification of endogenous compounds that modulate or activate intrinsic neuronal populations to induce cellular protec-

cardiac pathogenesis as well as risk of cardiac arrhythmias and sudden death [83, 84].

repeated defibrillation are involved in ganglion pathology [99].

tion remains a priority.

44 Autonomic Nervous System

Sudden cardiac death due to ventricular arrhythmias is highly relevant to cardiovascular disease related mortality [113]; autonomic neuronal dysfunction is a major contributor to induction of atrial and ventricular dysrhythmias [114–116]. Pathologically induced disturbances in neural processing within the cardiac neural hierarchy affect efferent neuronal outputs throughout the myocardium [19, 117] (i.e. intrinsic and extrinsic cardiac ganglia, central reflexes [95, 118–121]). Cardiac neurons are generally classified as afferent, efferent or convergent on the basis of responses to various cardiovascular stimuli [31, 120]. A study from Ardell's laboratory examined functional remodeling of neuronal elements within the context of myocardial infarction [120]; they showed that: (1) morphological and phenotypic remodeling of intracardiac ganglia is dependent on the site of injury, (2) attenuation of afferent neural signals to intrinsic cardiac neurons (i.e. within ischemic zone) but preservation of these signals in remote and border regions (i.e. neural sensory border zone), (3) autonomic efferent inputs to intrinsic cardiac neurons are maintained, (4) transduction capacity increases in convergent intrinsic local circuit neurons (of the heart) and (5) connectivity of intrinsic cardiac neurons is reduced. Current findings suggest that neuronal remodeling can occur independently of direct injury to specific neuron subsets; as such, neuronal plasticity within the cardiac neuroaxis is crucial post-infarction and during progression of cardiovascular disease [122, 123]. Indeed, healed myocardium provides a particular challenge to electrical propagation and regulation of cardiac function [124, 125]; abnormal cardiac efferent signaling results in continuous discord between central and peripheral aspects within the neural hierarchy that produces fatal arrhythmias due to excessive sympathoexcitation [122]. The peri-infarct region (i.e. interface between dense scar and surviving myocardium) also has an increased potential for ectopic beats [71, 126]. Ajijola and coworkers recently determined that (1) despite scarring, myocyte loss and ion channel remodeling significant regulation of electrical activation occurs via cardiac sympathetic nerves within the peri-infarct region, and (2) there is significant remodeling of sympathetic innervation within the anteroapical region [127]; additionally, they emphasized the critical role of adrenergic activation in modulating propagation patterns.

**5. Therapeutic interventions**

nerve remodeling [134, 135, 137, 170].

**5.2. Non-pharmacological**

Pharmacologic interventions can play an important role in post-ischemic nerve repair; though most medications reduce the incidence of arrhythmias some can be proarrhythmic [165]. Significant improvement in acute and chronic ischemic cardiomyopathy, myocarditis and vagus nerve remodeling have recently been reported in clinical and experimental studies with different pharmacological approaches such as epidermal growth factor neuregulin-1 (NRG1) [134, 138, 166–168]. NRG1 is a key factor for cardiac development [136, 169]; NRG1 activates tyrosine kinase causing a host of cardiovascular effects: (1) regulation of structure and function in cardiomyocytes (i.e. apoptosis, cell proliferation), (2) promotion of angiogenesis and (3) downregulation of sympathetic nerve mRNA and protein expression levels to inhibit

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Cardiovascular disease is often accompanied by increased activity of carotid body chemoreceptors, which induces an autonomic imbalance [161]; ablation of carotid bodies has been documented to markedly improve post-ischemic cardiovascular end-points in clinical and animal studies [159, 160, 171]. Catheter ablation techniques have been used effectively in patients with ventricular tachyarrhythmias [147]; in addition, bilateral cardiac stellate decentralization (removes excessive sympathetic input to cardiomyocytes) is used in subjects that do not respond to conventional treatments [158]. A drawback of the latter intervention is that it is permanent and generally accompanied by secondary effects [172]. Of note is that the ICNS preserves the ability to coordinate neural activity and electrical stability even after

Specific neuron subpopulations can be targeted for neuromodulation therapy [174–176]; spinal cord stimulation (SCS), vagus nerve stimulation (VNS) and bioelectronic therapy (i.e. chargebalanced direct current, axonal modulation, kilohertz (kHz) frequency alternating current, etc.) are used in ischemic heart disease patients to abate reflex activation of peripheral ganglia [118, 147, 148, 174, 177, 178]. Application of electric current by stimulation/suppression of action potential propagation along nerves modulates neuron and organ function [145, 179]. Blockade of action potential propagation is produced by either kHz frequency alternating current or direct current; these protocols are used repeatedly and safely in patients [145, 147, 180].

SCS stimulates sympathetic afferents to transduce signals, which initiate from the ischemic myocardium, to spinal cord dorsal horn neurons [121, 181]. In the majority of patients receiving this treatment beneficial effects (i.e. improved exercise capacity, quality of life, etc.) last for more than a year [182, 183]. Additionally, SCS augments resistance to stress in myocytes by modifying myocyte energetics [177, 184]; in our laboratory, we documented that concurrent

VNS, on the other hand, protects myocardium [185–187] through anti-adrenergic interactions (i.e. higher parasympathetic activity stimulates muscarinic receptor activation that

disconnection of inputs from higher central command (i.e. brain) [173].

SCS did not influence post-ischemic ventricular perfusion [150].

**5.1. Pharmacological**

Premature ventricular contractions (PVC; contraction of the ventricles caused by abnormal electrical activity) often lead to cardiovascular events, left ventricle dysfunction and sudden cardiac death [128]; multiple mechanisms have been proposed including mechanical dyssynchrony, abnormalities in calcium handling and oxygen consumption and autonomic imbalance [122, 129, 130]. Hamon and coworkers documented (using *in vivo* cardioneural mapping) that PVCs are a powerful stressor for the ICNS and that PVC-induced neural and electrophysiological changes are critical for arrhythmogenesis and remodeling. PVCs with variable coupling intervals have a more complex impact on cardiac neurons than those with fixed short or long coupling intervals [128]. The unpredictability of coupling intervals could trigger a sympathovagal imbalance that influences cardiomyocyte function and leads to electric instability. Greater neuronal responses (particularly within convergent neurons that are responsible for reflex processing) to variable compared to constant stimulus (i.e. neural adaptation) have been described in sensory neurons of the visual, auditory and olfactory systems [131, 132]. In the heart sympathetic nerve activity is greater during irregular cardiac pacing and is independent of hemodynamic changes [133]. As such, increased variability of PVC coupling interval could play a role in reflex activation of the ANS. Greater understanding of underlying mechanoelectric mechanisms of PVC-induced arrhythmogenesis should help to improve risk stratification in cardiac patients that would allow use of more aggressive pharmacologic and non-pharmacologic therapeutics (i.e. specifically targeting the ANS) in prophylactic management (cf. **Table 1**).


**Table 1.** Management strategies that target the autonomic nervous system.

## **5. Therapeutic interventions**

#### **5.1. Pharmacological**

Pharmacologic interventions can play an important role in post-ischemic nerve repair; though most medications reduce the incidence of arrhythmias some can be proarrhythmic [165]. Significant improvement in acute and chronic ischemic cardiomyopathy, myocarditis and vagus nerve remodeling have recently been reported in clinical and experimental studies with different pharmacological approaches such as epidermal growth factor neuregulin-1 (NRG1) [134, 138, 166–168]. NRG1 is a key factor for cardiac development [136, 169]; NRG1 activates tyrosine kinase causing a host of cardiovascular effects: (1) regulation of structure and function in cardiomyocytes (i.e. apoptosis, cell proliferation), (2) promotion of angiogenesis and (3) downregulation of sympathetic nerve mRNA and protein expression levels to inhibit nerve remodeling [134, 135, 137, 170].

#### **5.2. Non-pharmacological**

**Pertinent studies**

*Pharmacological interventions*

46 Autonomic Nervous System

prophylactic management (cf. **Table 1**).

*Non-pharmacological interventions*

• Neuregulin-1 [134–138] • Ghrelin [139] • Vasopressin [140] • Anesthetic preconditioning [141]

occurs via cardiac sympathetic nerves within the peri-infarct region, and (2) there is significant remodeling of sympathetic innervation within the anteroapical region [127]; additionally, they emphasized the critical role of adrenergic activation in modulating propagation patterns.

Premature ventricular contractions (PVC; contraction of the ventricles caused by abnormal electrical activity) often lead to cardiovascular events, left ventricle dysfunction and sudden cardiac death [128]; multiple mechanisms have been proposed including mechanical dyssynchrony, abnormalities in calcium handling and oxygen consumption and autonomic imbalance [122, 129, 130]. Hamon and coworkers documented (using *in vivo* cardioneural mapping) that PVCs are a powerful stressor for the ICNS and that PVC-induced neural and electrophysiological changes are critical for arrhythmogenesis and remodeling. PVCs with variable coupling intervals have a more complex impact on cardiac neurons than those with fixed short or long coupling intervals [128]. The unpredictability of coupling intervals could trigger a sympathovagal imbalance that influences cardiomyocyte function and leads to electric instability. Greater neuronal responses (particularly within convergent neurons that are responsible for reflex processing) to variable compared to constant stimulus (i.e. neural adaptation) have been described in sensory neurons of the visual, auditory and olfactory systems [131, 132]. In the heart sympathetic nerve activity is greater during irregular cardiac pacing and is independent of hemodynamic changes [133]. As such, increased variability of PVC coupling interval could play a role in reflex activation of the ANS. Greater understanding of underlying mechanoelectric mechanisms of PVC-induced arrhythmogenesis should help to improve risk stratification in cardiac patients that would allow use of more aggressive pharmacologic and non-pharmacologic therapeutics (i.e. specifically targeting the ANS) in

• Transcutaneous electrical nerve stimulation (TENS) [142–144] • Bioelectronic block [145–148] • Spinal cord stimulation (SCS) [118, 149–152] • Vagal nerve stimulation (VNS) [78, 153, 154] • Renal nerve denervation [155–157] • Cardiac decentralization and carotid body ablation [158–162] • Cardiac conditioning (ischemia, exercise) [21, 163, 164]

**Table 1.** Management strategies that target the autonomic nervous system.

Cardiovascular disease is often accompanied by increased activity of carotid body chemoreceptors, which induces an autonomic imbalance [161]; ablation of carotid bodies has been documented to markedly improve post-ischemic cardiovascular end-points in clinical and animal studies [159, 160, 171]. Catheter ablation techniques have been used effectively in patients with ventricular tachyarrhythmias [147]; in addition, bilateral cardiac stellate decentralization (removes excessive sympathetic input to cardiomyocytes) is used in subjects that do not respond to conventional treatments [158]. A drawback of the latter intervention is that it is permanent and generally accompanied by secondary effects [172]. Of note is that the ICNS preserves the ability to coordinate neural activity and electrical stability even after disconnection of inputs from higher central command (i.e. brain) [173].

Specific neuron subpopulations can be targeted for neuromodulation therapy [174–176]; spinal cord stimulation (SCS), vagus nerve stimulation (VNS) and bioelectronic therapy (i.e. chargebalanced direct current, axonal modulation, kilohertz (kHz) frequency alternating current, etc.) are used in ischemic heart disease patients to abate reflex activation of peripheral ganglia [118, 147, 148, 174, 177, 178]. Application of electric current by stimulation/suppression of action potential propagation along nerves modulates neuron and organ function [145, 179]. Blockade of action potential propagation is produced by either kHz frequency alternating current or direct current; these protocols are used repeatedly and safely in patients [145, 147, 180].

SCS stimulates sympathetic afferents to transduce signals, which initiate from the ischemic myocardium, to spinal cord dorsal horn neurons [121, 181]. In the majority of patients receiving this treatment beneficial effects (i.e. improved exercise capacity, quality of life, etc.) last for more than a year [182, 183]. Additionally, SCS augments resistance to stress in myocytes by modifying myocyte energetics [177, 184]; in our laboratory, we documented that concurrent SCS did not influence post-ischemic ventricular perfusion [150].

VNS, on the other hand, protects myocardium [185–187] through anti-adrenergic interactions (i.e. higher parasympathetic activity stimulates muscarinic receptor activation that limits excess adrenergic receptor activation [188]) within intrinsic cardiac ganglia [189, 190] combined with reduced release of norepinephrine from presynaptic mechanisms in ischemic myocardium [191]. VNS also influences myocyte energetics due to its regulatory effects on glycogen metabolism [78, 185]; all of these factors can change sensory transduction within the cardiac milieu in the event of disparities between oxygen and nutrient supply and demand.

**Conflict of interest**

**Author details**

John G. Kingma1,2\*, Denys Simard2

Laval, Québec, QC, Canada

**References**

The authors have no conflicts of interest to declare.

\*Address all correspondence to: john.kingma@fmed.ulaval.ca

1986;**57**(4):299-309. PubMed PMID: 3946219

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2017;**207**:48-58. DOI: 10.1016/j.autneu.2017.07.008

CIRCRESAHA.113.300308. PubMed PMID: 23989716

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<69::AID-JEMT6>3.0.CO;2-N

and Jacques R. Rouleau1,2

Autonomic Nervous System and Neurocardiac Physiopathology

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49

1 Department of Medicine, Faculty of Medicine, Laval University, Québec, QC, Canada

2 Centre de Recherche de l'institut de Cardiologie et de Pneumologie du Québec, Université

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Salavation and co-workers have examined potential differences between SCS and VNS with regard to their ability to alter cardiac sensory neurons in nodose ganglia to transduce the ischemic myocardium; they reported that these interventions differentially obtund nociceptive-related nodose afferent neuronal inputs to the medulla but do not affect mechanosensitive transduction capabilities [192]. These nerve stimulation techniques are presently being tested in a number of clinical trials in heart failure patients (i.e. NECTAR-HF, ANTHEM-HF, INOVATE-HF) with promising results [153, 193, 194].

Intact neural pathways may be unimportant for protection of ischemic myocardium; this is most apparent in the transplanted heart where autonomic ganglia are disconnected from central neurons [121, 195]. Endogenous compounds released into the bloodstream or locally near nerves, neurons and cardiomyocytes, etc. during ischemia could stimulate intracellular pathways that transduce cytoprotective mechanisms. For instance, cardiac conditioning, which significantly delays development of post-ischemic tissue injury [91, 196–198], might involve activation of the ICNS (cf. recent review [90]). A variety of conditioning stratagems (both pharmacologic and non-pharmacologic) that trigger cellular transduction pathways (guanylate cyclase, kinases, etc.) mediate cellular protection through end-effectors; significant cross-tolerance exists with regard to the mechanisms involved [106, 199, 200].

### **6. Conclusions**

Neurocardiology involves dynamic exchange between neurohumoral control systems and the cardiac milieu; bi-directional interactions between sympathetic and parasympathetic efferent pathways regulate inter-organ communications at different levels of the neuraxis. This is evident in the cardiac conditioning paradigm (i.e. pre-, per-, post- and remote) where endogenous ligands and catecholamines trigger intracellular transduction pathways to mediate cytoprotective end-effectors that promote cell survival [201, 202]. Strategies that protect against non-lethal ischemic injury could depend on nervous system status the question of how cytoprotective signals are transmitted between organs remains crucial. New findings support the concept that disorders within the ANS contribute to pathogenesis of organ injury, co-morbidities [203, 204] and even survival. Improved comprehension of modifications within the cardiac-neuro axis at the molecular, cellular, organ and whole body levels are critical for development of therapeutic strategies.

### **Acknowledgements**

The authors would like to thank Professor Chantale Simard, Faculty of Pharmacy at Laval University for helpful suggestions during the preparation of this review.

#### **Conflict of interest**

limits excess adrenergic receptor activation [188]) within intrinsic cardiac ganglia [189, 190] combined with reduced release of norepinephrine from presynaptic mechanisms in ischemic myocardium [191]. VNS also influences myocyte energetics due to its regulatory effects on glycogen metabolism [78, 185]; all of these factors can change sensory transduction within the cardiac milieu in the event of disparities between oxygen and nutrient supply and demand. Salavation and co-workers have examined potential differences between SCS and VNS with regard to their ability to alter cardiac sensory neurons in nodose ganglia to transduce the ischemic myocardium; they reported that these interventions differentially obtund nociceptive-related nodose afferent neuronal inputs to the medulla but do not affect mechanosensitive transduction capabilities [192]. These nerve stimulation techniques are presently being tested in a number of clinical trials in heart failure patients (i.e. NECTAR-HF, ANTHEM-HF,

Intact neural pathways may be unimportant for protection of ischemic myocardium; this is most apparent in the transplanted heart where autonomic ganglia are disconnected from central neurons [121, 195]. Endogenous compounds released into the bloodstream or locally near nerves, neurons and cardiomyocytes, etc. during ischemia could stimulate intracellular pathways that transduce cytoprotective mechanisms. For instance, cardiac conditioning, which significantly delays development of post-ischemic tissue injury [91, 196–198], might involve activation of the ICNS (cf. recent review [90]). A variety of conditioning stratagems (both pharmacologic and non-pharmacologic) that trigger cellular transduction pathways (guanylate cyclase, kinases, etc.) mediate cellular protection through end-effectors; significant

Neurocardiology involves dynamic exchange between neurohumoral control systems and the cardiac milieu; bi-directional interactions between sympathetic and parasympathetic efferent pathways regulate inter-organ communications at different levels of the neuraxis. This is evident in the cardiac conditioning paradigm (i.e. pre-, per-, post- and remote) where endogenous ligands and catecholamines trigger intracellular transduction pathways to mediate cytoprotective end-effectors that promote cell survival [201, 202]. Strategies that protect against non-lethal ischemic injury could depend on nervous system status the question of how cytoprotective signals are transmitted between organs remains crucial. New findings support the concept that disorders within the ANS contribute to pathogenesis of organ injury, co-morbidities [203, 204] and even survival. Improved comprehension of modifications within the cardiac-neuro axis at the molecular, cellular, organ and whole body levels are critical for

The authors would like to thank Professor Chantale Simard, Faculty of Pharmacy at Laval

University for helpful suggestions during the preparation of this review.

cross-tolerance exists with regard to the mechanisms involved [106, 199, 200].

INOVATE-HF) with promising results [153, 193, 194].

**6. Conclusions**

48 Autonomic Nervous System

development of therapeutic strategies.

**Acknowledgements**

The authors have no conflicts of interest to declare.

#### **Author details**

John G. Kingma1,2\*, Denys Simard2 and Jacques R. Rouleau1,2

\*Address all correspondence to: john.kingma@fmed.ulaval.ca

1 Department of Medicine, Faculty of Medicine, Laval University, Québec, QC, Canada

2 Centre de Recherche de l'institut de Cardiologie et de Pneumologie du Québec, Université Laval, Québec, QC, Canada

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**Chapter 4**

**Provisional chapter**

**Inflammation and Autonomic Function**

**Inflammation and Autonomic Function**

DOI: 10.5772/intechopen.79280

Inflammation is generally a temporary and limited condition but may lead to a chronic one if immune and physiological homeostasis are disrupted. The autonomic nervous system has an important role in the short- and, also, long-term regulation of homeostasis and, thus, on inflammation. Autonomic modulation in acute and chronic inflammation has been implicated with a sympathetic interference in the earlier stages of the inflammatory process and the activation of the vagal inflammatory reflex to regulate innate immune responses and cytokine functional effects in longer processes. The present review focuses on the autonomic mechanisms controlling proinflammatory responses, and we will discuss novel therapeutic options linked to autonomic modulation for dis-

Inflammation is the physiological response to invading pathogens and tissue damage, such as exposure to extreme heat or cold, ischemia, and trauma [1, 2]. The inflammatory response can be divided into acute or chronic inflammation. An acute inflammatory response is a controlled process, with a short time window of minutes up to a few hours and it is characterized by the abundant presence of a specific type of immune competent cells (neutrophils), responsible for clearing invading pathogens and promote tissue repair, thus restoring homeostasis. However, uncontrolled inflammation, which extends from days up to years, may cause more severe complications. In the latter, if an accumulation of lymphocytes in the inflamed tissue predominates,

eases associated with a chronic inflammatory condition such as sepsis.

anti-inflammatory pathway, inflammatory reflex, sepsis

**Keywords:** inflammation, autonomic nervous system, heart rate variability,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Ângela Leal, Mafalda Carvalho, Isabel Rocha and

Ângela Leal, Mafalda Carvalho, Isabel Rocha and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79280

Helder Mota-Filipe

Helder Mota-Filipe

**Abstract**

**1. Introduction**

#### **Inflammation and Autonomic Function Inflammation and Autonomic Function**

Ângela Leal, Mafalda Carvalho, Isabel Rocha and Helder Mota-Filipe Ângela Leal, Mafalda Carvalho, Isabel Rocha and Helder Mota-Filipe

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79280

#### **Abstract**

Inflammation is generally a temporary and limited condition but may lead to a chronic one if immune and physiological homeostasis are disrupted. The autonomic nervous system has an important role in the short- and, also, long-term regulation of homeostasis and, thus, on inflammation. Autonomic modulation in acute and chronic inflammation has been implicated with a sympathetic interference in the earlier stages of the inflammatory process and the activation of the vagal inflammatory reflex to regulate innate immune responses and cytokine functional effects in longer processes. The present review focuses on the autonomic mechanisms controlling proinflammatory responses, and we will discuss novel therapeutic options linked to autonomic modulation for diseases associated with a chronic inflammatory condition such as sepsis.

DOI: 10.5772/intechopen.79280

**Keywords:** inflammation, autonomic nervous system, heart rate variability, anti-inflammatory pathway, inflammatory reflex, sepsis

#### **1. Introduction**

Inflammation is the physiological response to invading pathogens and tissue damage, such as exposure to extreme heat or cold, ischemia, and trauma [1, 2]. The inflammatory response can be divided into acute or chronic inflammation. An acute inflammatory response is a controlled process, with a short time window of minutes up to a few hours and it is characterized by the abundant presence of a specific type of immune competent cells (neutrophils), responsible for clearing invading pathogens and promote tissue repair, thus restoring homeostasis. However, uncontrolled inflammation, which extends from days up to years, may cause more severe complications. In the latter, if an accumulation of lymphocytes in the inflamed tissue predominates,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

both immune and physiological homeostasis are disrupted, thereby the inflammation can progress to a chronic condition [1, 2]. In its most severe form, it can lead to permanent tissue damage, organ dysfunction, and, ultimately, death [3]. The immune cells residing in tissues, i.e., macrophages, fibroblasts, mast cells, and dendritic cells, as well as circulating leukocytes, including monocytes and neutrophils, recognize pathogen invasion and/or cell damage with intracellular or surface-expressed pattern recognition receptors (PRRs). These receptors detect, either directly or indirectly, pathogen-associated molecular patterns (PAMPs), such as, microbial nucleic acids, lipoproteins, and carbohydrates, often essential for microbe survival, or damage-associated molecular patterns (DAMPs), endogenous molecules normally found in cells, that are released during necrosis contributing to sterile inflammation. Activated PRRs in response to PAMPs and DAMPs, oligomerize and assemble large multisubunit factors, such as, nuclear factor kappa B (NF-kB), activator protein 1 (AP1), cellular transcription factor (CREB), CCAAT-enhancerbinding proteins (c/EBP), and interferon regulatory factors (IRF) transcription factors, which will in turn initiate complex downstream signaling cascades, resulting in the increased expression of key pro- and anti-inflammatory genes [2, 3]. For instance, protease caspase-1, activated by a subset of PRRs, causes maturation of cytokines interleukins IL-1b and IL-18.

parts of the nervous system. Indeed, recent studies indicate that systemic inflammation can

Inflammation and Autonomic Function http://dx.doi.org/10.5772/intechopen.79280 69

The autonomic nervous system (ANS) includes the sympathetic and parasympathetic nervous system (SNS and PNS, respectively) as its motor systems, and regulates and integrates many human physiological systems and functions, such as the cardiovascular system, the endocrine and exocrine systems, and the digestive system [14, 15]. As reviewed by Kenney and Ganta, to balance the functions of autonomic effector organs, the SNS and PNS work antagonistically, synergistically, or independently [14]. Previous studies have shown that both the SNS and PNS can sense inflammation and influence development and severity of

There are many chronic autoimmune diseases in which there is an imbalance of the ANS, for example, rheumatoid arthritis (RA), caused by synovial inflammation, leading to bone erosions, cartilage damage, and ultimately joint deformities and disability [8, 12]. Patients with RA have autonomic modifications, with lower parasympathetic activity and less frequently, alterations in sympathetic function [17]. These alterations are correlated with higher levels of inflammatory markers, such as C-reactive protein (CRP) concentrations and erythrocyte sedimentation rate [17, 18]. Another example is obesity, which consists in the accumulation of abnormal and excessive fat that may interfere with the maintenance of an optimal state of health and is accompanied by an increased morbidity and mortality [19]. This condition is generally associated with other clinical comorbidities including, cardiovascular impairment, atherosclerosis, insulin resistance, and diabetes mellitus [19, 20]. The excess of macronutrients in the adipose tissues stimulates them to release inflammatory mediators (TNFα, Il-6) and reduces production of adiponectin, predisposing to a pro-inflammatory state and oxidative stress [20]. The ANS has a significant role in the integrated short-term regulation of weight, modulating the satiety signal and energy expenditure. The afferent vagal pathways are probably the most important link between the gut and the brain and interact in a complex way with gut hormones. SNS has the physiological function of increasing lipolysis and energy expenditure, through sympathetic innervation in white and brown adipose tissues. However, in obesity, SNS activity is compromised and might trigger alterations in sympathetic regulation of cardiovascular function, thus favoring the development of cardiovascular complica-

Another two examples of immune/inflammatory diseases are sepsis and severe burn injury, both characterized by severe global changes to the entire immune system [25]. The immunopathological response to the intense disruptions to the body's homeostatic balance can contribute to the development of systemic inflammatory response syndrome (SIRS), serious metabolic disturbances, and subsequent multiple organ failure and death [25, 26]. During the acute phase, following burn injury, there is an increase in sympathetic activity, which is important for the modulation of energy substrate mobilization, cardiovascular, and hemodynamic compensation and wound repair [27]. Nevertheless, prolonged or excessive sympathetic activity due to the activation of positive feedback mechanism can also be deleterious [27]. Furthermore, the increased susceptibility to infection and other systemic disorders are also accompanied by excessive inflammatory responses that underline the observed cardiac dysfunction, acute respiratory distress syndrome, acute renal failure, increased intestinal permeability resulting in bacterial translocation, hypermetabolism, hypercatabolism, and ultimately, sepsis [28, 29]. Sepsis can, therefore, be

be attenuated by the autonomic nerve fibers [14].

inflammatory processes in animal models [12, 16].

tions, such as hypertension [21, 22] and organ dysfunction [23, 24].

Expression of genes encoding enzymes, chemokines, cytokines, adhesion molecules, and regulators of the extracellular matrix promotes the further recruitment and activation of leukocytes to the region, which are crucial for eliminating foreign particles and host debris [2, 3]. Cell adhesion molecules and chemokines facilitate leukocyte extravasation from the circulation to the affected site, the chemokines stimulating G-protein-coupled receptors (GPCRs) [3]. Thus, the immune system plays a crucial and defining role in the overall inflammatory response processes through recruitment of various immune cell types, in addition to the release of pro-inflammatory cytokines into the bloodstream, including interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFα), which are inhibited by mediators of inflammation resolution, such as anti-inflammatory cytokines, that restore cellular homeostasis and defend the organism from external injuries [2].

The interaction between nervous and immune systems, or the "supersystems" as described by Tada [4], is, in fact, critical in the maintenance and regulation of homeostasis, not only under a daily routine, but also, in adverse environmental conditions caused by injury, infections, and exposure to toxins [5–7]. Indeed, the autonomic nervous system controls the inflammatory processes and immune responses, by finding a balance between pro-inflammatory and antiinflammatory responses, ensuring an adequate host defense with minimal collateral damage due to overly aggressive responses of the innate immune system [6]. Both parasympathetic and sympathetic efferent nerves have been suggested to affect immune cells and inflammatory responses. The latter interfere in the earlier stages of the inflammatory process, while the parasympathetic nervous system is important to regulate innate immune responses and cytokine functional effects in chronic processes [6, 8, 9].

#### **2. Autonomic nervous system and inflammation**

Over the last few years, association between inflammation and common human diseases (e.g., sepsis, obesity, diabetes, rheumatoid arthritis) remains an unsolved mystery of current biology and medicine [10–13]. Inflammation as a response to infection interacts with different parts of the nervous system. Indeed, recent studies indicate that systemic inflammation can be attenuated by the autonomic nerve fibers [14].

both immune and physiological homeostasis are disrupted, thereby the inflammation can progress to a chronic condition [1, 2]. In its most severe form, it can lead to permanent tissue damage, organ dysfunction, and, ultimately, death [3]. The immune cells residing in tissues, i.e., macrophages, fibroblasts, mast cells, and dendritic cells, as well as circulating leukocytes, including monocytes and neutrophils, recognize pathogen invasion and/or cell damage with intracellular or surface-expressed pattern recognition receptors (PRRs). These receptors detect, either directly or indirectly, pathogen-associated molecular patterns (PAMPs), such as, microbial nucleic acids, lipoproteins, and carbohydrates, often essential for microbe survival, or damage-associated molecular patterns (DAMPs), endogenous molecules normally found in cells, that are released during necrosis contributing to sterile inflammation. Activated PRRs in response to PAMPs and DAMPs, oligomerize and assemble large multisubunit factors, such as, nuclear factor kappa B (NF-kB), activator protein 1 (AP1), cellular transcription factor (CREB), CCAAT-enhancerbinding proteins (c/EBP), and interferon regulatory factors (IRF) transcription factors, which will in turn initiate complex downstream signaling cascades, resulting in the increased expression of key pro- and anti-inflammatory genes [2, 3]. For instance, protease caspase-1, activated

68 Autonomic Nervous System

by a subset of PRRs, causes maturation of cytokines interleukins IL-1b and IL-18.

homeostasis and defend the organism from external injuries [2].

cytokine functional effects in chronic processes [6, 8, 9].

**2. Autonomic nervous system and inflammation**

Expression of genes encoding enzymes, chemokines, cytokines, adhesion molecules, and regulators of the extracellular matrix promotes the further recruitment and activation of leukocytes to the region, which are crucial for eliminating foreign particles and host debris [2, 3]. Cell adhesion molecules and chemokines facilitate leukocyte extravasation from the circulation to the affected site, the chemokines stimulating G-protein-coupled receptors (GPCRs) [3]. Thus, the immune system plays a crucial and defining role in the overall inflammatory response processes through recruitment of various immune cell types, in addition to the release of pro-inflammatory cytokines into the bloodstream, including interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFα), which are inhibited by mediators of inflammation resolution, such as anti-inflammatory cytokines, that restore cellular

The interaction between nervous and immune systems, or the "supersystems" as described by Tada [4], is, in fact, critical in the maintenance and regulation of homeostasis, not only under a daily routine, but also, in adverse environmental conditions caused by injury, infections, and exposure to toxins [5–7]. Indeed, the autonomic nervous system controls the inflammatory processes and immune responses, by finding a balance between pro-inflammatory and antiinflammatory responses, ensuring an adequate host defense with minimal collateral damage due to overly aggressive responses of the innate immune system [6]. Both parasympathetic and sympathetic efferent nerves have been suggested to affect immune cells and inflammatory responses. The latter interfere in the earlier stages of the inflammatory process, while the parasympathetic nervous system is important to regulate innate immune responses and

Over the last few years, association between inflammation and common human diseases (e.g., sepsis, obesity, diabetes, rheumatoid arthritis) remains an unsolved mystery of current biology and medicine [10–13]. Inflammation as a response to infection interacts with different The autonomic nervous system (ANS) includes the sympathetic and parasympathetic nervous system (SNS and PNS, respectively) as its motor systems, and regulates and integrates many human physiological systems and functions, such as the cardiovascular system, the endocrine and exocrine systems, and the digestive system [14, 15]. As reviewed by Kenney and Ganta, to balance the functions of autonomic effector organs, the SNS and PNS work antagonistically, synergistically, or independently [14]. Previous studies have shown that both the SNS and PNS can sense inflammation and influence development and severity of inflammatory processes in animal models [12, 16].

There are many chronic autoimmune diseases in which there is an imbalance of the ANS, for example, rheumatoid arthritis (RA), caused by synovial inflammation, leading to bone erosions, cartilage damage, and ultimately joint deformities and disability [8, 12]. Patients with RA have autonomic modifications, with lower parasympathetic activity and less frequently, alterations in sympathetic function [17]. These alterations are correlated with higher levels of inflammatory markers, such as C-reactive protein (CRP) concentrations and erythrocyte sedimentation rate [17, 18]. Another example is obesity, which consists in the accumulation of abnormal and excessive fat that may interfere with the maintenance of an optimal state of health and is accompanied by an increased morbidity and mortality [19]. This condition is generally associated with other clinical comorbidities including, cardiovascular impairment, atherosclerosis, insulin resistance, and diabetes mellitus [19, 20]. The excess of macronutrients in the adipose tissues stimulates them to release inflammatory mediators (TNFα, Il-6) and reduces production of adiponectin, predisposing to a pro-inflammatory state and oxidative stress [20]. The ANS has a significant role in the integrated short-term regulation of weight, modulating the satiety signal and energy expenditure. The afferent vagal pathways are probably the most important link between the gut and the brain and interact in a complex way with gut hormones. SNS has the physiological function of increasing lipolysis and energy expenditure, through sympathetic innervation in white and brown adipose tissues. However, in obesity, SNS activity is compromised and might trigger alterations in sympathetic regulation of cardiovascular function, thus favoring the development of cardiovascular complications, such as hypertension [21, 22] and organ dysfunction [23, 24].

Another two examples of immune/inflammatory diseases are sepsis and severe burn injury, both characterized by severe global changes to the entire immune system [25]. The immunopathological response to the intense disruptions to the body's homeostatic balance can contribute to the development of systemic inflammatory response syndrome (SIRS), serious metabolic disturbances, and subsequent multiple organ failure and death [25, 26]. During the acute phase, following burn injury, there is an increase in sympathetic activity, which is important for the modulation of energy substrate mobilization, cardiovascular, and hemodynamic compensation and wound repair [27]. Nevertheless, prolonged or excessive sympathetic activity due to the activation of positive feedback mechanism can also be deleterious [27]. Furthermore, the increased susceptibility to infection and other systemic disorders are also accompanied by excessive inflammatory responses that underline the observed cardiac dysfunction, acute respiratory distress syndrome, acute renal failure, increased intestinal permeability resulting in bacterial translocation, hypermetabolism, hypercatabolism, and ultimately, sepsis [28, 29]. Sepsis can, therefore, be an associated comorbidity of burn injuries, but in its essence is a highly common heterogeneous syndrome in the general population and will be further reviewed in Section 3 [25].

Several studies have demonstrated the role of the SNS in inflammation. Martelli et al. showed that in a rat model of intravenous endotoxin, a bilateral section of splenic sympathetic nerves deeply increases inflammatory cytokine release; however, bilateral vagotomy was ineffective, which suggests a splanchnic sympathetic efferent reflex arc of the anti-inflammatory neural pathway [31]. Another clinical phenomenon is immunosuppression after stroke [32]. Indeed, the 6-hydroxydopamine, which blocks a nonselective α-adrenoreceptor and causes pharmacological ablation of the SNS, may also attenuate stroke-induced immunological abnormalities, prevent infections, and improve the survival, and thus SNS activation, instead of the PNS, has a significant role in the immunosuppression response [6, 32–34]. Additionally, in hypertensive patients, the central inhibition of the SNS decreased peripheral TNF serum levels [35]. Moreover, del Rey and colleagues have also found in an animal model of arthritis that during protracted inflammation, there might be a disruption of this communication between the brain and the immune system [36]. There are also several studies indicating that the sympathetic nervous system might be influencing different forms of cancer [37]. In fact, epidemiological studies showed that breast cancer and melanoma improve with the use of beta-blockers, while other studies imply that psychological stress might modulate SNS activity, with a significant impact on inflammation and consequently on the pathogenesis of some

Inflammation and Autonomic Function http://dx.doi.org/10.5772/intechopen.79280 71

Finally, recent studies show that the SNS plays a significant role in several immune-mediated or immune-related diseases, including sepsis [39], colitis [40], allergic asthma [41], chronic eye

The parasympathetic nervous system (PSNS) innervates multiple organ systems, including cardiovascular, respiratory, immune, and endocrine systems [43] and plays a critical role in a diverse array of physiological processes, such as inflammation, immune response, heart rate, gastrointestinal peristalsis, and digestion [13]. About 75% of parasympathetic innervation comes from the tenth cranial nerve, the vagus nerve (VN), that extends throughout the body, and is the largest nerve and main parasympathetic division of the autonomic nervous system [13, 30, 44]. Vagus nerve comprises both sensory afferent neurons, crucial for conducting peripheral immune signals to the brain, which integrate the visceral sensory information and coordinates the autonomic function and visceral activity [13, 33, 34], and motor efferent neurons, which integrate the information that was delivered to the central nervous system and control the peripheral effectors [30, 45]. The vagus nerve not only regulates gut physiology but also mediates cholinergic anti-inflammatory pathway, the inflammatory reflex that controls immune function, and pro-inflammatory responses during infection and injury [35, 45, 46]. The sensory afferent vagus nerve fibers detect peripheral inflammatory mediators, such as cytokines, released by activated macrophages and other immune cells, revealing its pro-inflammatory properties; however, a potent anti-inflammatory effect is exhibited by the efferent branch [46]. The animal models of acute inflammation reveal that the activation of the efferent vagus nerve, probably due to binding of acetylcholine on the alpha-7 subunitcontaining nicotinic receptors (α7nAChR), essential for the vagal anti-inflammatory action [47, 48] resulted in reduced systemic production of pro-inflammatory cytokines [46, 49]. This suggests that in the initial phase of inflammation processes, the neuroimmune path eliminates the infectious agent, and in the posterior phase re-establishes the homeostasis [13, 33, 34, 50].

**2.2. The role of parasympathetic nervous system in the inflammatory processes**

cancers [37, 38].

inflammation [42], arthritis [8, 36], among others.

#### **2.1. The role of sympathetic nervous system in the inflammatory processes**

The sympathetic nervous system (SNS) is responsible for the "fight-or-flight" response to threatening situations and consists of neural hardwiring emanating from the spinal cord to innervate target organs, including primary and secondary lymphoid organs. About 25% of sympathetic nerve fibers arise from cranial nerves III, VII, and IX and from the second and third sacral spinal nerves [30]. Diverse stimuli (stressors, cytokines, and infection) trigger the SNS and consequent catecholamine release, inducing functional alterations in immune system susceptibility to respond to an invasive infection and other pathologies. As previously mentioned, the SNS interacts in several different manners with the immune system to maintain immune homeostasis under basal conditions, by enhancing host defenses to eliminate pathogens, promoting healing after tissue injury, and restoring homeostasis after pathogen elimination and/or tissue repair. This communication with all immune competent cells occurs directly by stimulated release of its major neurotransmitter, i.e., norepinephrine—NE, and subsequent intercellular signaling via postsynaptic adrenergic receptors (ARs) expressed in closely apposed immunocytes, i.e., T and B lymphocytes, antigenpresenting cells, stromal cells, granulocytes, macrophages, and mast cells [15]. The SNS is highly adaptive, and to appropriately regulate the immune system, it acts through the:


In the initial stages of the inflammatory processes, the body assumes an "inflammatory configuration" with increased systemic SNS and hypothalamic-pituitary-adrenal (HPA) axis activity through the chemoreceptor reflex, the ultimate protective, which can be interpreted as an "energy appeal reaction," resulting in the provision of enough energy-rich fuels, like glucose and free fatty acids, to fulfill the needs of an activated immune system together with the maintenance of appropriate oxygen blood levels. If inflammation evolves to a more severe state, the system changes into a "chronic inflammatory condition," that, according to Pongratz and Straub, is characterized by an increased systemic activity of the SNS, an increased activity of the HPA axis but without immunosuppression (glucocorticoid receptor desensitization and inadequacy), and a local repulsion of SNS fibers from inflamed tissue, including lymphoid organs, to create zones of permitted inflammation [8]. The immune response is more or less uncoupled from central regulation to avoid the anti-inflammatory influence of the brain. All mechanisms ensure an optimal fight against an invading antigen. Nevertheless, if a prolonged or inappropriate activation of either the SNS or immune system persists, the effects are detrimental and can result in the collapse of these two systems, ultimately failing in re-establishing immune system homeostasis within normal physiological ranges [8, 15]. Under such conditions, the immune system and/or SNS can promote pathological and lethal effects, including chronic inflammation, toxic shock, tissue damage, immune deficiency, autoimmunity, and cancer [15], as well as, cachexia, high blood pressure, insulin resistance, leading to increased levels of cardiovascular mortality [8].

Several studies have demonstrated the role of the SNS in inflammation. Martelli et al. showed that in a rat model of intravenous endotoxin, a bilateral section of splenic sympathetic nerves deeply increases inflammatory cytokine release; however, bilateral vagotomy was ineffective, which suggests a splanchnic sympathetic efferent reflex arc of the anti-inflammatory neural pathway [31]. Another clinical phenomenon is immunosuppression after stroke [32]. Indeed, the 6-hydroxydopamine, which blocks a nonselective α-adrenoreceptor and causes pharmacological ablation of the SNS, may also attenuate stroke-induced immunological abnormalities, prevent infections, and improve the survival, and thus SNS activation, instead of the PNS, has a significant role in the immunosuppression response [6, 32–34]. Additionally, in hypertensive patients, the central inhibition of the SNS decreased peripheral TNF serum levels [35]. Moreover, del Rey and colleagues have also found in an animal model of arthritis that during protracted inflammation, there might be a disruption of this communication between the brain and the immune system [36]. There are also several studies indicating that the sympathetic nervous system might be influencing different forms of cancer [37]. In fact, epidemiological studies showed that breast cancer and melanoma improve with the use of beta-blockers, while other studies imply that psychological stress might modulate SNS activity, with a significant impact on inflammation and consequently on the pathogenesis of some cancers [37, 38].

an associated comorbidity of burn injuries, but in its essence is a highly common heterogeneous

The sympathetic nervous system (SNS) is responsible for the "fight-or-flight" response to threatening situations and consists of neural hardwiring emanating from the spinal cord to innervate target organs, including primary and secondary lymphoid organs. About 25% of sympathetic nerve fibers arise from cranial nerves III, VII, and IX and from the second and third sacral spinal nerves [30]. Diverse stimuli (stressors, cytokines, and infection) trigger the SNS and consequent catecholamine release, inducing functional alterations in immune system susceptibility to respond to an invasive infection and other pathologies. As previously mentioned, the SNS interacts in several different manners with the immune system to maintain immune homeostasis under basal conditions, by enhancing host defenses to eliminate pathogens, promoting healing after tissue injury, and restoring homeostasis after pathogen elimination and/or tissue repair. This communication with all immune competent cells occurs directly by stimulated release of its major neurotransmitter, i.e., norepinephrine—NE, and subsequent intercellular signaling via postsynaptic adrenergic receptors (ARs) expressed in closely apposed immunocytes, i.e., T and B lymphocytes, antigenpresenting cells, stromal cells, granulocytes, macrophages, and mast cells [15]. The SNS is highly adaptive, and to appropriately regulate the immune system, it acts through the:

**1.** Constant up- and down-regulation of diverse target cell functions across time (i.e., expan-

**2.** Detection and interaction with the diverse signaling pathways that mediate the above cel-

In the initial stages of the inflammatory processes, the body assumes an "inflammatory configuration" with increased systemic SNS and hypothalamic-pituitary-adrenal (HPA) axis activity through the chemoreceptor reflex, the ultimate protective, which can be interpreted as an "energy appeal reaction," resulting in the provision of enough energy-rich fuels, like glucose and free fatty acids, to fulfill the needs of an activated immune system together with the maintenance of appropriate oxygen blood levels. If inflammation evolves to a more severe state, the system changes into a "chronic inflammatory condition," that, according to Pongratz and Straub, is characterized by an increased systemic activity of the SNS, an increased activity of the HPA axis but without immunosuppression (glucocorticoid receptor desensitization and inadequacy), and a local repulsion of SNS fibers from inflamed tissue, including lymphoid organs, to create zones of permitted inflammation [8]. The immune response is more or less uncoupled from central regulation to avoid the anti-inflammatory influence of the brain. All mechanisms ensure an optimal fight against an invading antigen. Nevertheless, if a prolonged or inappropriate activation of either the SNS or immune system persists, the effects are detrimental and can result in the collapse of these two systems, ultimately failing in re-establishing immune system homeostasis within normal physiological ranges [8, 15]. Under such conditions, the immune system and/or SNS can promote pathological and lethal effects, including chronic inflammation, toxic shock, tissue damage, immune deficiency, autoimmunity, and cancer [15], as well as, cachexia, high blood pressure, insulin resistance, leading to increased levels of cardiovascular mortality [8].

sion, differentiation, apoptosis, and cytokine secretion) and

lular functions [14].

70 Autonomic Nervous System

syndrome in the general population and will be further reviewed in Section 3 [25].

**2.1. The role of sympathetic nervous system in the inflammatory processes**

Finally, recent studies show that the SNS plays a significant role in several immune-mediated or immune-related diseases, including sepsis [39], colitis [40], allergic asthma [41], chronic eye inflammation [42], arthritis [8, 36], among others.

#### **2.2. The role of parasympathetic nervous system in the inflammatory processes**

The parasympathetic nervous system (PSNS) innervates multiple organ systems, including cardiovascular, respiratory, immune, and endocrine systems [43] and plays a critical role in a diverse array of physiological processes, such as inflammation, immune response, heart rate, gastrointestinal peristalsis, and digestion [13]. About 75% of parasympathetic innervation comes from the tenth cranial nerve, the vagus nerve (VN), that extends throughout the body, and is the largest nerve and main parasympathetic division of the autonomic nervous system [13, 30, 44]. Vagus nerve comprises both sensory afferent neurons, crucial for conducting peripheral immune signals to the brain, which integrate the visceral sensory information and coordinates the autonomic function and visceral activity [13, 33, 34], and motor efferent neurons, which integrate the information that was delivered to the central nervous system and control the peripheral effectors [30, 45]. The vagus nerve not only regulates gut physiology but also mediates cholinergic anti-inflammatory pathway, the inflammatory reflex that controls immune function, and pro-inflammatory responses during infection and injury [35, 45, 46]. The sensory afferent vagus nerve fibers detect peripheral inflammatory mediators, such as cytokines, released by activated macrophages and other immune cells, revealing its pro-inflammatory properties; however, a potent anti-inflammatory effect is exhibited by the efferent branch [46]. The animal models of acute inflammation reveal that the activation of the efferent vagus nerve, probably due to binding of acetylcholine on the alpha-7 subunitcontaining nicotinic receptors (α7nAChR), essential for the vagal anti-inflammatory action [47, 48] resulted in reduced systemic production of pro-inflammatory cytokines [46, 49]. This suggests that in the initial phase of inflammation processes, the neuroimmune path eliminates the infectious agent, and in the posterior phase re-establishes the homeostasis [13, 33, 34, 50].

In human studies, the parasympathetic neurotransmitter acetylcholine attenuated proinflammatory cytokine release (e.g., TNFα) in lipopolysaccharide-stimulated macrophage cultures [49], so nicotine was more effective than muscarine in inhibiting TNF release. Human macrophages express α7nAChR subunit, and its knockdown makes macrophages less responsive to nicotine-mediated TNF inhibition [49].

in experimental glomerulonephritis, a genetic α7nAChR deletion exacerbates inflammation and fibrosis [6, 54]. Recently, Cedillo et al. showed that increased α7nAChR expression on peripheral blood mononuclear cells was associated with better control of inflammation, dis-

Inflammation and Autonomic Function http://dx.doi.org/10.5772/intechopen.79280 73

Concluding, both animal and human studies have suggested that the vagus nerve stimulation has a potential protective regulating systemic inflammation in various pathologies, such as ischemia/reperfusion, sepsis, epilepsy, hemorrhagic shock, migraine, and others [13, 51, 59–61]. However, additional studies are needed to determine the interplay between the vagus and the splenic nerves, and their respective roles in modulating inflammation [6, 12]. According to Martelli et al., several treatments are currently undergoing development,

Sepsis is an important cause of admission in intensive care units (ICU) and remains a major clinical and scientific challenge in modern medicine [53]; this is a huge and expensive medical problem throughout the world, with a mortality rate ranging between 30 and 50% [10, 62]. It is defined as life-threatening acute organ dysfunction, secondary to infection [63], characterized by abnormal body temperature, mental confusion, hypotension, diminished urine output, or thrombocytopenia [53, 63]. Over the past two and a half decades, there has been a tremendous effort to develop standardized diagnostic definitions of sepsis, as described in (**Table 1**). The most prevalent sites of infection, responsible to trigger sepsis in humans, are the lungs, abdominal cavity, urinary tract, and primary infections of the blood stream. After the unsuccessful treatment of sepsis, the patient may develop circulatory, cellular, and metabolic abnormalities, such as, respiratory or renal failure, changes in coagulation, and profound and unresponsive hypotension [53], as well as modifications in cardiovascular, autonomic, neurological, hormonal, metabolic and clotting systems [72, 73]. These marked alterations are characterized by septic shock, the

The pathophysiology of sepsis is characterized as a host reaction to infection that involves a balanced inflammatory response, critical to fight the infection, and an unregulated pro- and anti-inflammatory response to induce organ damage in the host [73]. Thereby, the immune response in sepsis results in the increased levels of cytokines, designated hyperinflammatory phase and subsequently evolves to hypoinflammatory phase (immune-suppressive function) [39], the latter being more destructive and aggressive than the initial infection [73]. This imbalance is determined by several factors, such as pathogen virulence, bacterial (i.e., lipoteichoic acid and bacterial lipopolysaccharide—LPS) [74] and patient-related factors (i.e., genetic background, age, and comorbidities) [53], leading the immune system to detect PAMPs (including components of bacterial, fungal, and viral pathogens) and DAMPS (endogenous molecules released from damaged host cells, including ATP, mitochondrial DNA, and high mobility group box 1 or HMGB1) [75]. For transcription of type I interferons and proinflammatory cytokines (i.e., TNF-8, interleukin (IL)-1, and IL-6) initiation, both DAMPs and PAMPs activate innate immune and some epithelial cells through pattern recognition receptors on the

ease severity, and clinical outcome in septic patients and prognosis [58].

based on the cholinergic anti-inflammatory pathway [46].

**3. Autonomic function and sepsis**

leading causes of death in sepsis [63].

Activating efferent vagus nerve can significantly suppress systemic pro-inflammatory cytokine levels in endotoxemia animal models, as the acetylcholine (Ach) released from the nerve terminals binds to the α7n-AChR expressed on macrophages, to modulate the immune system response [51]. α7nAChR, expressed in the nervous and immune systems, is important for mediating anti-inflammatory signaling by inhibiting NF-κB nuclear translocation and activating the JAK2/STAT3 pathway [48, 49, 51], being also a crucial neural component connecting the parasympathetic vagus nerve with the sympathetic splenic nerve at the mesenteric ganglion [52]. The endotoxemia animal model reveals that peripheral vagal afferents can be activated by responding directly to bacterial lipopolysaccharide (LPS) and cytokines, such as TNFα, interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-gamma (IFN-γ). IL-1 receptors, expressed on vagal afferents, can be activated by inflammatory stimulation to regulate the immune responses [23, 48]. It has been shown that an excess of proinflammatory cytokine was released in α7nAChR knockout mice, and macrophages from these animals fail to respond to cholinergic agonists [6, 48]. Further, electrical vagus nerve stimulation reduced systemic TNFα concentrations and prevented septic shock in rats [49], and in mice, the vagus nerve stimulation (VNS), as well as splenic nerve electrical stimulation, inhibits lipopolysaccharide (LPS)-induced TNFα release [49, 50, 52, 53]; however, those results were quite surprising because the spleen does not have vagal innervation [53].

Several experiments demonstrated that the sympathetic splenic nerve connects the vagus nerve to the spleen [47, 52]. It is possible that the α7nAchR regulates both the neuronal connection and the macrophage activation. Moreover, the connection between the vagus and splenic nerves has been a matter of constant debate [43]. For example, anatomical and physiological studies have demonstrated no connection between the vagus and splenic nerves [54]. Additionally, denervation of the arterial splenic nerve in mice led to the inhibition of the cholinergic anti-inflammatory pathway [52]. To resolve this inhibition is essential to find a non-neural link in the anti-inflammatory pathway from vagus to spleen. Some authors have proposed an unconventional and theoretical model, where vagus nerve stimulation activates multiple cell types, the choline acetyltransferase positive (CHAT+), epithelial cells, endothelial cells, muscle fibers, and immune cells (such as lymphocytes and macrophages) that are not resident in the spleen, migrating in direction of this organ and subsequently releasing acetylcholine [12, 46, 55]. This electrical nerve stimulation therapy could be applied concomitantly with a pharmacological treatment for a better response. The human studies reveal that the great advantage of this model is the stimulation of ACh/norepinephrine release, reducing interventions with higher doses of anti-inflammatory drugs or even halting their administration [56].

In addition, it has been shown that other organs display a cholinergic control of inflammation, such as gut, kidney, and liver. Despite lung exhibiting vagal innervation, activation of the cholinergic anti-inflammatory pathway is not sufficient to regulate inflammation; however, it is necessary to maintain the homeostasis. In this sense, vagus and/or splenic nerve stimulation appeared as an efficient procedure to minimize inflammation [57]. Furthermore, in experimental glomerulonephritis, a genetic α7nAChR deletion exacerbates inflammation and fibrosis [6, 54]. Recently, Cedillo et al. showed that increased α7nAChR expression on peripheral blood mononuclear cells was associated with better control of inflammation, disease severity, and clinical outcome in septic patients and prognosis [58].

Concluding, both animal and human studies have suggested that the vagus nerve stimulation has a potential protective regulating systemic inflammation in various pathologies, such as ischemia/reperfusion, sepsis, epilepsy, hemorrhagic shock, migraine, and others [13, 51, 59–61]. However, additional studies are needed to determine the interplay between the vagus and the splenic nerves, and their respective roles in modulating inflammation [6, 12]. According to Martelli et al., several treatments are currently undergoing development, based on the cholinergic anti-inflammatory pathway [46].

#### **3. Autonomic function and sepsis**

In human studies, the parasympathetic neurotransmitter acetylcholine attenuated proinflammatory cytokine release (e.g., TNFα) in lipopolysaccharide-stimulated macrophage cultures [49], so nicotine was more effective than muscarine in inhibiting TNF release. Human macrophages express α7nAChR subunit, and its knockdown makes macrophages less responsive to

Activating efferent vagus nerve can significantly suppress systemic pro-inflammatory cytokine levels in endotoxemia animal models, as the acetylcholine (Ach) released from the nerve terminals binds to the α7n-AChR expressed on macrophages, to modulate the immune system response [51]. α7nAChR, expressed in the nervous and immune systems, is important for mediating anti-inflammatory signaling by inhibiting NF-κB nuclear translocation and activating the JAK2/STAT3 pathway [48, 49, 51], being also a crucial neural component connecting the parasympathetic vagus nerve with the sympathetic splenic nerve at the mesenteric ganglion [52]. The endotoxemia animal model reveals that peripheral vagal afferents can be activated by responding directly to bacterial lipopolysaccharide (LPS) and cytokines, such as TNFα, interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-gamma (IFN-γ). IL-1 receptors, expressed on vagal afferents, can be activated by inflammatory stimulation to regulate the immune responses [23, 48]. It has been shown that an excess of proinflammatory cytokine was released in α7nAChR knockout mice, and macrophages from these animals fail to respond to cholinergic agonists [6, 48]. Further, electrical vagus nerve stimulation reduced systemic TNFα concentrations and prevented septic shock in rats [49], and in mice, the vagus nerve stimulation (VNS), as well as splenic nerve electrical stimulation, inhibits lipopolysaccharide (LPS)-induced TNFα release [49, 50, 52, 53]; however, those results were quite surprising

Several experiments demonstrated that the sympathetic splenic nerve connects the vagus nerve to the spleen [47, 52]. It is possible that the α7nAchR regulates both the neuronal connection and the macrophage activation. Moreover, the connection between the vagus and splenic nerves has been a matter of constant debate [43]. For example, anatomical and physiological studies have demonstrated no connection between the vagus and splenic nerves [54]. Additionally, denervation of the arterial splenic nerve in mice led to the inhibition of the cholinergic anti-inflammatory pathway [52]. To resolve this inhibition is essential to find a non-neural link in the anti-inflammatory pathway from vagus to spleen. Some authors have proposed an unconventional and theoretical model, where vagus nerve stimulation activates multiple cell types, the choline acetyltransferase positive (CHAT+), epithelial cells, endothelial cells, muscle fibers, and immune cells (such as lymphocytes and macrophages) that are not resident in the spleen, migrating in direction of this organ and subsequently releasing acetylcholine [12, 46, 55]. This electrical nerve stimulation therapy could be applied concomitantly with a pharmacological treatment for a better response. The human studies reveal that the great advantage of this model is the stimulation of ACh/norepinephrine release, reducing interventions with higher doses of anti-inflammatory

In addition, it has been shown that other organs display a cholinergic control of inflammation, such as gut, kidney, and liver. Despite lung exhibiting vagal innervation, activation of the cholinergic anti-inflammatory pathway is not sufficient to regulate inflammation; however, it is necessary to maintain the homeostasis. In this sense, vagus and/or splenic nerve stimulation appeared as an efficient procedure to minimize inflammation [57]. Furthermore,

nicotine-mediated TNF inhibition [49].

72 Autonomic Nervous System

because the spleen does not have vagal innervation [53].

drugs or even halting their administration [56].

Sepsis is an important cause of admission in intensive care units (ICU) and remains a major clinical and scientific challenge in modern medicine [53]; this is a huge and expensive medical problem throughout the world, with a mortality rate ranging between 30 and 50% [10, 62]. It is defined as life-threatening acute organ dysfunction, secondary to infection [63], characterized by abnormal body temperature, mental confusion, hypotension, diminished urine output, or thrombocytopenia [53, 63]. Over the past two and a half decades, there has been a tremendous effort to develop standardized diagnostic definitions of sepsis, as described in (**Table 1**). The most prevalent sites of infection, responsible to trigger sepsis in humans, are the lungs, abdominal cavity, urinary tract, and primary infections of the blood stream. After the unsuccessful treatment of sepsis, the patient may develop circulatory, cellular, and metabolic abnormalities, such as, respiratory or renal failure, changes in coagulation, and profound and unresponsive hypotension [53], as well as modifications in cardiovascular, autonomic, neurological, hormonal, metabolic and clotting systems [72, 73]. These marked alterations are characterized by septic shock, the leading causes of death in sepsis [63].

The pathophysiology of sepsis is characterized as a host reaction to infection that involves a balanced inflammatory response, critical to fight the infection, and an unregulated pro- and anti-inflammatory response to induce organ damage in the host [73]. Thereby, the immune response in sepsis results in the increased levels of cytokines, designated hyperinflammatory phase and subsequently evolves to hypoinflammatory phase (immune-suppressive function) [39], the latter being more destructive and aggressive than the initial infection [73]. This imbalance is determined by several factors, such as pathogen virulence, bacterial (i.e., lipoteichoic acid and bacterial lipopolysaccharide—LPS) [74] and patient-related factors (i.e., genetic background, age, and comorbidities) [53], leading the immune system to detect PAMPs (including components of bacterial, fungal, and viral pathogens) and DAMPS (endogenous molecules released from damaged host cells, including ATP, mitochondrial DNA, and high mobility group box 1 or HMGB1) [75]. For transcription of type I interferons and proinflammatory cytokines (i.e., TNF-8, interleukin (IL)-1, and IL-6) initiation, both DAMPs and PAMPs activate innate immune and some epithelial cells through pattern recognition receptors on the


first and local responses is the release of vasoactive peptides by spinal afferent C-fibers and the ensuing neurogenic inflammation. Vagal afferent C-fibers can exert neurogenic inflammatory reflex actions, like those underlying some forms of diarrhea; however, in the proposed vagal anti-inflammatory reflex, the exact role of efferent parasympathetic vagal fibers remains to be elucidated, as these fibers do not seem to directly innervate the major immune organs [79, 80]. The work developed by Tracey and colleagues have shown that, in animal models of sepsis and in another inflammatory conditions (e.g., colitis, hemorrhagic shock, and ischemia-reperfusion injury), neural reflex involving the vagus nerve causes T cells to release acetylcholine and, therefore, interacts with the α7nAch receptor on macrophages to dampen the release of powerful proinflammatory mediators such as TNF-α and HMGB-1 [49, 50, 81]. In an animal model of cecal ligation puncture (CLP), improvements in survival and suppression of the SIRS response of sepsis were described after stimulation of the vagal nerve [81], as does the use of a selective or a universal synthetic agonist for α7nAchR on macrophages [49]. Another recent work indicates that vagal stimulation also reduces symptoms and inflamma-

Inflammation and Autonomic Function http://dx.doi.org/10.5772/intechopen.79280 75

tion in patients suffering from rheumatoid arthritis and Crohn's disease [80].

in experimental sepsis [85].

Contrary to the lack of information on vagal innervation of immune organs and cells, there is longstanding evidence in favor of sympathetic nervous system innervation of primary and secondary immune organs (including, thymus, spleen, bone marrow, and lymph nodes) [82]. Depending on the kind of bacterial infection, there are different effects of SNS on bacterial dissemination, innate immune cell responses, and inflammatory mediators [83]. During septic systemic inflammation, noradrenaline increases in immune organs where it can act on α and β receptors present on macrophages, and adrenaline release into the blood also increases, implying that almost any tissue macrophage could be exposed to adrenaline, which has been shown to modulate pro-inflammatory cytokine secretion by cultured blood cells [81]. Noradrenaline, which is both released and often administered during sepsis [84], may, along with adrenaline, exert pro-inflammatory actions through stimulation of β1 adrenergic receptors, as antagonists of this receptor have been shown to exert anti-inflammatory effects

These findings show a specific interest, since, in clinical severe sepsis and septic shock, the selective β1 receptor blocker, esmolol, has shown beneficial effects on microcirculation and myocardial oxygen [84, 85]. Interestingly, in a rat model of CLP, esmolol has similar beneficial effects on vascular and cardiac function [86], and at the same time, it increases anti-inflammatory and reduces pro-inflammatory cytokine production, reduces bacterial component, and improves gut barrier function, ultimately increasing animal survival rates [87]. Although the SNS can influence infection-induced immune responses, depending on the type of bacteria and the timing of treatment, this kind of adrenergic drugs may have beneficial or detrimental effects on the active molecules. Notwithstanding, the promising anti-inflammatory effects of the β1

Several advancements have been made over time to understand the neuroimmune mechanisms for maintaining and restoring homeostasis during normal and pathophysiologic conditions.

antagonist esmolol need to be confirmed in clinical trials on septic patients [80].

**4. Autonomic modulation and therapeutics in sepsis**

**Table 1.** Sepsis: previous and revised definition.

cell surface (toll-like receptors and C-type lectin receptors) or in the cytosol (NOD-like receptors, RIG-I-like receptors) [76, 77]. In the case of bacterial infection, when a microbiological diagnosis is made, about half of the cases show that 60% are caused by Gram-negative and Gram-positive bacterium in the remaining cases [53, 62, 78]. Lipopolysaccharide (LPS) from Gram-negative bacteria (an example of a PAMP) reacts with toll-like receptor 4 (TLR4), causing phagocytic cells to robustly generate a variety of proinflammatory cytokines signaling, leading to systemic inflammatory response syndrome (SIRS) [10].

In sepsis, not only the response of immune cells is highly context dependent to stimuli, but also, the nervous system itself depends on the inflammatory context [10]. Several evidences demonstrate that immune and inflammatory responses are regulated by the autonomic nervous system through PNS and SNS activities [8, 14]. Essentially, to inhibit the inflammatory cytokine production by innate immune cells in the spleen, gut, and other organ, the carotid body chemoreceptors, afferent sensory vagal fibers, and brain areas with a permeable blood barrier respond to local and systemic cytokines, signaling to brainstem nuclei, which in turn send vagal, cholinergic efferents to the periphery [10, 79]. After bacterial infection, one of the first and local responses is the release of vasoactive peptides by spinal afferent C-fibers and the ensuing neurogenic inflammation. Vagal afferent C-fibers can exert neurogenic inflammatory reflex actions, like those underlying some forms of diarrhea; however, in the proposed vagal anti-inflammatory reflex, the exact role of efferent parasympathetic vagal fibers remains to be elucidated, as these fibers do not seem to directly innervate the major immune organs [79, 80]. The work developed by Tracey and colleagues have shown that, in animal models of sepsis and in another inflammatory conditions (e.g., colitis, hemorrhagic shock, and ischemia-reperfusion injury), neural reflex involving the vagus nerve causes T cells to release acetylcholine and, therefore, interacts with the α7nAch receptor on macrophages to dampen the release of powerful proinflammatory mediators such as TNF-α and HMGB-1 [49, 50, 81]. In an animal model of cecal ligation puncture (CLP), improvements in survival and suppression of the SIRS response of sepsis were described after stimulation of the vagal nerve [81], as does the use of a selective or a universal synthetic agonist for α7nAchR on macrophages [49]. Another recent work indicates that vagal stimulation also reduces symptoms and inflammation in patients suffering from rheumatoid arthritis and Crohn's disease [80].

Contrary to the lack of information on vagal innervation of immune organs and cells, there is longstanding evidence in favor of sympathetic nervous system innervation of primary and secondary immune organs (including, thymus, spleen, bone marrow, and lymph nodes) [82]. Depending on the kind of bacterial infection, there are different effects of SNS on bacterial dissemination, innate immune cell responses, and inflammatory mediators [83]. During septic systemic inflammation, noradrenaline increases in immune organs where it can act on α and β receptors present on macrophages, and adrenaline release into the blood also increases, implying that almost any tissue macrophage could be exposed to adrenaline, which has been shown to modulate pro-inflammatory cytokine secretion by cultured blood cells [81]. Noradrenaline, which is both released and often administered during sepsis [84], may, along with adrenaline, exert pro-inflammatory actions through stimulation of β1 adrenergic receptors, as antagonists of this receptor have been shown to exert anti-inflammatory effects in experimental sepsis [85].

These findings show a specific interest, since, in clinical severe sepsis and septic shock, the selective β1 receptor blocker, esmolol, has shown beneficial effects on microcirculation and myocardial oxygen [84, 85]. Interestingly, in a rat model of CLP, esmolol has similar beneficial effects on vascular and cardiac function [86], and at the same time, it increases anti-inflammatory and reduces pro-inflammatory cytokine production, reduces bacterial component, and improves gut barrier function, ultimately increasing animal survival rates [87]. Although the SNS can influence infection-induced immune responses, depending on the type of bacteria and the timing of treatment, this kind of adrenergic drugs may have beneficial or detrimental effects on the active molecules. Notwithstanding, the promising anti-inflammatory effects of the β1 antagonist esmolol need to be confirmed in clinical trials on septic patients [80].

#### **4. Autonomic modulation and therapeutics in sepsis**

cell surface (toll-like receptors and C-type lectin receptors) or in the cytosol (NOD-like receptors, RIG-I-like receptors) [76, 77]. In the case of bacterial infection, when a microbiological diagnosis is made, about half of the cases show that 60% are caused by Gram-negative and Gram-positive bacterium in the remaining cases [53, 62, 78]. Lipopolysaccharide (LPS) from Gram-negative bacteria (an example of a PAMP) reacts with toll-like receptor 4 (TLR4), causing phagocytic cells to robustly generate a variety of proinflammatory cytokines signaling,

>2 mmol/L (18 mg/dL) despite adequate fluid resuscitation

In sepsis, not only the response of immune cells is highly context dependent to stimuli, but also, the nervous system itself depends on the inflammatory context [10]. Several evidences demonstrate that immune and inflammatory responses are regulated by the autonomic nervous system through PNS and SNS activities [8, 14]. Essentially, to inhibit the inflammatory cytokine production by innate immune cells in the spleen, gut, and other organ, the carotid body chemoreceptors, afferent sensory vagal fibers, and brain areas with a permeable blood barrier respond to local and systemic cytokines, signaling to brainstem nuclei, which in turn send vagal, cholinergic efferents to the periphery [10, 79]. After bacterial infection, one of the

leading to systemic inflammatory response syndrome (SIRS) [10].

**Sepsis definitions**

74 Autonomic Nervous System

Previous definitions [64–68]

Systemic inflammatory response syndrome (SIRS)

Revised definitions [63, 69, 70]

Diagnosis Signs

**Table 1.** Sepsis: previous and revised definition.

Diagnosis Signs and symptoms

Sepsis SIRS and proven or suspected infection

(36 mg/dL)

infection

organ dysfunction)

**Two of the following symptoms**: • Body temperature > 38 or < 36°C • Heart rate > 90 beats/min

• White blood cell count >12.000/mm<sup>3</sup>

Septic shock Sepsis and persistent hypotension (mean arterial pressure [MAP] <65 mmHg) after fluid resuscitation and/or lactate >4 mmol

Sepsis • Life-threatening organ dysfunction caused by a dysregulated host response to

Septic shock • Septic shock is a subset of sepsis in which underlying circulatory and cellular/

Severe sepsis Sepsis in combination with multiple organ dysfunction (MODS).

• Respiratory rate > 20 breaths/min or arterial CO<sup>2</sup> < 32 mmHg

, <4000/mm<sup>3</sup>

• Suspected or documented infection and an acute increase of >2 sequential (sepsis related) organ failure assessment (SOFA) points (SOFA score [71] is a proxy for

metabolic abnormalities are profound enough to substantially increase mortality • Sepsis and vasopressor therapy needed to increase MAP ≥65 mmHg and lactate

or > 10% immature forms

Several advancements have been made over time to understand the neuroimmune mechanisms for maintaining and restoring homeostasis during normal and pathophysiologic conditions. Some studies have already reported that, in adverse conditions, basic reflex mechanisms respond through efferent vagal and sympathetic circuits and that neurotransmitters influence leukocytes with important clinical implications [8, 43, 88]. In this heading, we will review the most relevant therapies associated with autonomic modulation, developed and tested over the last 3 years.

Regarding the importance of sympathetic downstream signaling in anti-inflammation processes, one promising pharmacological approach is the inhibition of phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP [89]. It is reported that, by inhibiting this enzyme, the cAMP increases, and, consequently, shows promising results in several diseases, as psoriatic arthritis, rheumatoid arthritis, Behçet's syndrome [90], and sepsis [91]. Focusing on sepsis studies, inhibitors of PDE4 reduce systemic vascular resistance and improve cardiac contractility and renal function [91]. PDE4 inhibitors also have a potent anti-inflammatory activity effect, by reducing microvascular leakage, all of which could be beneficial in infants with severe sepsis [92]. **Table 2** summarizes the main treatments developed in the last 3 years based on pharmacologic PDE inhibition in sepsis.

It is known that studies in humans have their limitations and confounding variables, such as, differences between groups in age and sex, body mass index, disease severity, smoking, frailty, and physical activity [97]. However, interestingly, clinical responses could be attained through autonomic nervous system modulation, as well as pro- and anti-inflammatory interventions [6, 98]. Several approaches, such as lifestyle interventions, medications, and devices, could be repurposed or further expanded to target inflammation. For example, to lessen systemic inflammation, in metabolic and cardiovascular diseases, it is necessary to develop measures to attenuate sympathetic activity [6, 98, 99]. Similarly, observations in animal models showed that sympathetic inhibition could improve the immunosuppression associated with strokes, and thereby, prevent infectious complications and deaths [6]. At the moment, there are some clinical trials in progress, to evaluate the effects of the cholinergic anti-inflammatory pathway by vagus nerve stimulation in patients with sepsis, severe sepsis, and shock septic, but there are also, at least, five clinical trials that are evaluating the oxytocin in endotoxemia model (https://clinicaltrials.gov/ct2/results?cond=Sepsis&term=esmolol&cntry=&state=&city=&dist).

Taking into account the cholinergic anti-inflammatory pathway, the major discoveries have been associated with: vagus nerve stimulation (VNS) and transvenous vagus nerve stimulation (tVNS) in anti-inflammatory responses, the identification of α7nAChRs in different cell types (macrophages, dendritic cells, and microglial cells) as targets for suppression of inflammation, and the integration of cholinergic T cells into the efferent neuroimmune pathway within the spleen, and also, some pharmacological approaches [98]. Although the vagal neuroimmune pathway is still controversial in specific situations (e.g., sterile or pathogeninduced inflammation), the effect of vagal stimulation could be beneficial to the host by inhibiting exacerbated cytokine production and inappropriate neutrophil entrapment into vital organs [12, 16]. By contrast, the cholinergic anti-inflammatory pathway can inhibit specific innate immune responses that are crucial to eliminate the bacteria (e.g., initial neutrophil migration) and subsequently increase the mortality in sepsis [100, 101]. Nevertheless, while VNS will unlikely replace the standard intensive care therapy, it is quite possible that, in the future, autonomic modulation through VNS would become an adjunct to benefit septic

**Pharmacological approach**

**Target**

> DibutyrylcAMP

Inhibition of

phosphodiesterase 4B

**(PDE4)**

Rolipram

Roflumilast

Roflumilast

Rolipram

Investigate potential

*In vitro* (cells of

LPS (1 μg/

ml)

horses)

antiendotoxic effects

Azithromycin

Ethyl

pyruvate

Metformin

Rolipram

Impact of the PDE4

Animal (rat)

LPS

Improvement of hepatic

Further studies needed to determine

2015

[96]

Inflammation and Autonomic Function http://dx.doi.org/10.5772/intechopen.79280 77

clinical applicability of PD-4-I

microcirculation and integrity

Protective effect on hepatoma cell

line viability

(2.5 mg/kg,

i.v.)

inhibition on hepatic

integrity

**Table 2.**

Pharmacologic phosphodiesterase (PDEs) inhibition in sepsis disease.

Effects on a CLP-modelinduced sepsis

Animal (mice)

CLP

Reduce of bacterial load

sepsis

Needed more studies.

May be an appropriate treatment of

2017

[94]

Inhibition of the IL-6 and TNFα

expression

Alleviation of liver injury

Rolipram: the most potent

Further work is required to investigate

2015

[95]

the potential use in

 vivo.

inhibitor of cytokine production

**Study** *In vitro:*

macrophage cell

(10 ng/ml)

vitro and in vivo

Mice: LPS

(10 mg/kg)

line (mouse)

Animal (mice)

**Method** Cell: LPS

Upregulates anti-inflammatory

cytokine IL-1Ra production

 in

**Conclusions**

**Perspectives** PDE4B-selective inhibitors may retain

the anti-inflammatory effects of

nonselective PDE4 inhibitors

**Year**

2017

[93]


Some studies have already reported that, in adverse conditions, basic reflex mechanisms respond through efferent vagal and sympathetic circuits and that neurotransmitters influence leukocytes

therapies associated with autonomic modulation, developed and tested over the last 3 years.

Regarding the importance of sympathetic downstream signaling in anti-inflammation pro

cesses, one promising pharmacological approach is the inhibition of phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP [89]. It is reported that, by inhibiting this enzyme, the cAMP increases, and, consequently, shows promising results in several diseases, as pso

riatic arthritis, rheumatoid arthritis, Behçet's syndrome [90], and sepsis [91]. Focusing on sepsis studies, inhibitors of PDE4 reduce systemic vascular resistance and improve cardiac contractility and renal function [91]. PDE4 inhibitors also have a potent anti-inflammatory activity effect, by reducing microvascular leakage, all of which could be beneficial in infants

It is known that studies in humans have their limitations and confounding variables, such as, differences between groups in age and sex, body mass index, disease severity, smoking, frailty, and physical activity [97]. However, interestingly, clinical responses could be attained through autonomic nervous system modulation, as well as pro- and anti-inflammatory interventions [6, 98]. Several approaches, such as lifestyle interventions, medications, and devices, could be repurposed or further expanded to target inflammation. For example, to lessen systemic inflammation, in metabolic and cardiovascular diseases, it is necessary to develop measures

that sympathetic inhibition could improve the immunosuppression associated with strokes,

clinical trials in progress, to evaluate the effects of the cholinergic anti-inflammatory pathway by vagus nerve stimulation in patients with sepsis, severe sepsis, and shock septic, but there are also, at least, five clinical trials that are evaluating the oxytocin in endotoxemia model (https://clinicaltrials.gov/ct2/results?cond=Sepsis&term=esmolol&cntry=&state=&city=&dist).

Taking into account the cholinergic anti-inflammatory pathway, the major discoveries have been associated with: vagus nerve stimulation (VNS) and transvenous vagus nerve stimu

lation (tVNS) in anti-inflammatory responses, the identification of α7nAChRs in different cell types (macrophages, dendritic cells, and microglial cells) as targets for suppression of inflammation, and the integration of cholinergic T cells into the efferent neuroimmune path

way within the spleen, and also, some pharmacological approaches [98]. Although the vagal neuroimmune pathway is still controversial in specific situations (e.g., sterile or pathogeninduced inflammation), the effect of vagal stimulation could be beneficial to the host by inhibiting exacerbated cytokine production and inappropriate neutrophil entrapment into vital organs [12, 16]. By contrast, the cholinergic anti-inflammatory pathway can inhibit spe

cific innate immune responses that are crucial to eliminate the bacteria (e.g., initial neutrophil migration) and subsequently increase the mortality in sepsis [100, 101]. Nevertheless, while VNS will unlikely replace the standard intensive care therapy, it is quite possible that, in the future, autonomic modulation through VNS would become an adjunct to benefit septic

8, 43, 88]. In this heading, we will review the most relevant

**2** summarizes the main treatments developed in the last 3 years

6, 98, 99]. Similarly, observations in animal models showed

6]. At the moment, there are some






with important clinical implications [

76 Autonomic Nervous System

with severe sepsis [92]. **Table**

to attenuate sympathetic activity [

based on pharmacologic PDE inhibition in sepsis.

and thereby, prevent infectious complications and deaths [

**Table 2.** Pharmacologic phosphodiesterase (PDEs) inhibition in sepsis disease.


**Target** Pharmacological intervention

Esmolol

Effects on reducing

Animal (rat)

CLP

Reduces apoptosis and

Needed clinical trials to confirm the

2017

[87]

use of esmolol in sepsis treatment

inflammatory reaction and protect

key organs

apoptosis and

inflammation

Effect on tissue

Prospective

Continuous

Controlled heart rate reduced the

Requires further research.

2016

[84]

duration of mechanical ventilation

No significant effects on

circulatory or tissue perfusion

infusion of

esmolol via

central venous

catheter

cohort clinical

perfusion and the

clinical prognosis of

trial

patients with severe

sepsis

Effects on myocardial

Animal (rat)

CLP

Enhances intrinsic cardiac

Further investigation needed to

2015

[86]

determine the effects of β1-blockade

on other organ functions and

inflammatory patterns in septic shock.

These findings confirm the suitability

2017

[107]

2016

[108]

of the electrocardiogram-derived

respiration technique to obtain the

estimated respiration signal in rodent

models

contractility and improves

vascular responsiveness to

catecholamines

Potential cardioprotective peptide

Diminished tachypnea and restore

the cardiorespiratory interactions

Provokes a less anticorrelated

pattern in HRV

Decreased mean heart rate

Reduce lethargy and moderated

the hyperthermia

Xanomeline

Effect on brain

Animal (mice,

LPS (6

CLP

mg/kg, i.p)

Suppresses serum and splenic

Further studies centrally-acting M1

2015

[109]

mAChR agonists as experimental

therapeutic agents in a broader

spectrum of inflammatory conditions

TNF levels

Alleviates sickness behavior, and

increased survival

muscarinic acetylcholine

rat)

receptor (mAChR)-

mediated cholinergic

signaling

Other

ANS indices

Investigate how changes

Prospective

Follow-up during

Variability of heart rate

Further investigations are required to

2017

Inflammation and Autonomic Function http://dx.doi.org/10.5772/intechopen.79280

[110]

find specific associations with drug

dosage, namely, drugs acting on the

sympathetic system, and clinically

relevant outcomes

79

significantly increases in septic

shock patients presenting

improvement of organ function

from ICU day 1 to day 3.

observational

the first 3 days of ICU stay after

development of

septic shock

cohort study

in cardiovascular

indices can be a sign of

progression of organ

failure

**Table 3.**

Sepsis: autonomic modulation, therapeutics, and treatments based on the PNS therapy.

and vascular function

Oxytocin

Effects on the

Animal (rat)

LPS (0.1 mg/kg; intraperitoneally)

cardiorespiratory

activity

**Study**

**Method**

**Conclusions**

**Perspectives**

**Year**


**Target**

Autonomic modulation

Chemoreflex

Chemoreflex activation

Animal (rat)

LPS

Attenuates the use of TNFα, IL-1β, and IL-6 plasma levels

Methods to stimulate CSN, which is a

2017

78 Autonomic Nervous System

[102]

promising therapeutic strategy

Increases the IL-10 plasma levels

(1.5

mg/kg, i.v.)

Pharmacological

blockade

(methylatropine or

propranolol)

Assessed changes in

Animal

LPS

Attenuates the upregulation of

Provides a suggestive link between

2016

[103]

VNS and potential clinical

application to treat sepsis in preterm

infants

Requires more research

2015

[104]

IL-6 and TNFα

Viable alternative to antibiotics

(rat)

(0.5 mg/kg, intratracheally)

IL-6 and TNFα

Effects on

Animal (rat)

LPS (i.v.)

Activates anti-inflammatory

effect through cholinergic

pathway

Improves the cerebral function

Reduces systemic and cerebral

inflammatory reaction

VNS decreases the release of

Further development of therapeutic

2015

[105]

directed of inflammatory reflex

modulation, and immunosuppression

in chronic inflammatory diseases

Short-term tVNS does not modulate

2015

[106]

the innate immune response in

pro-inflammatory cytokines both

in serum and spleen

sepsis-associated

encephalopathy

Potential role of

Animal (mice)

LPS (2 mg/kg,

i.p.)

prostaglandin

in cholinergic

neuro-regulation

Determine the

Randomized

LPS (2 ng/kg,

tVNS is feasible and safe but

does not influence the systemic

inflammatory response in

 vivo

humans

Require more studies

The CAP activation in high-risk

2015[58]

septic patients has therapeutic

potential: this activation could be

used as an adjunctive therapy

double-blind

i.v).

feasibility and safety,

investigated its putative

study

anti-inflammatory

effects

α7 gene expression

Pilot study

Septic patients

PBMC α7 gene expression level

is a clinically relevant marker for

CAP activity in sepsis: the higher

the α7 expression, the better the

inflammation control and the

prognosis

within the

first 24 hours of diagnosing

sepsis

level in peripheral

blood mononuclear

cells (PBMC) as marker

for CAP

Transvenous

vagus nerve

stimulation (tVNS)

stimulation

and

pharmacological

intervention

Vagal nerve

stimulation

B(VNS)

**Study**

**Method**

**Conclusions**

**Perspectives**

**Year**

**Table 3.** Sepsis: autonomic modulation, therapeutics, and treatments based on the PNS therapy. patients [100, 101]. The most relevant treatments and therapies based on parasympathetic nervous system developed over the last 3 years, in animal models and human studies, are shown in **Table 3**.

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[1] Báez-Pagán CA, Delgado-Vélez M, Lasalde-Dominicci JA. Activation of the macrophage α7 nicotinic acetylcholine receptor and control of inflammation. Journal of Neuroimmune

Inflammation and Autonomic Function http://dx.doi.org/10.5772/intechopen.79280 81

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#### **5. Conclusion**

The nervous and immune systems are not fully independent. When the body is inflamed, both systems produce neurotransmitters and cytokines and express receptors that are involved in important physiological functions and in the maintenance of homeostasis. The reactions of the immune competent cells to neurotransmitters are variable, depending on the context of receptor engagement, such as, activation state of the cell, expression pattern of neurotransmitter receptors, microenvironment, cytokine, and distance from the catecholamine source (concentration). It is already well described that autonomic modulation in acute and chronic inflammation has been implicated with a sympathetic interference in the earlier stages of the inflammatory process and the activation of the vagal inflammatory reflex to regulate innate immune responses and cytokine functional effects in longer more chronic processes. The present chapter reviewed the overall autonomic mechanisms controlling inflammatory responses in several conditions such as, burn processes, arthritis rheumatoid, obesity, with a special focus on the inflammatory processes associated with sepsis. Furthermore, the most relevant therapeutic options for the latter, through autonomic modulation, were also reviewed and summarized.

In summary, it is quite clear that sepsis remains a worldwide clinical challenge and therapies' outcomes depend largely on host factors. Henceforth, continuous searching for new and more effective therapies during the initial phases of sepsis is utterly important, in order to reduce the mortality associated with this syndrome (condition).

### **Conflict of interest**

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

### **Author details**

Ângela Leal<sup>2</sup> \*, Mafalda Carvalho<sup>2</sup> , Isabel Rocha1,2 and Helder Mota-Filipe2,3

\*Address all correspondence to: araqueleal@hotmail.com


#### **References**

patients [100, 101]. The most relevant treatments and therapies based on parasympathetic nervous system developed over the last 3 years, in animal models and human studies, are

The nervous and immune systems are not fully independent. When the body is inflamed, both systems produce neurotransmitters and cytokines and express receptors that are involved in important physiological functions and in the maintenance of homeostasis. The reactions of the immune competent cells to neurotransmitters are variable, depending on the context of receptor engagement, such as, activation state of the cell, expression pattern of neurotransmitter receptors, microenvironment, cytokine, and distance from the catecholamine source (concentration). It is already well described that autonomic modulation in acute and chronic inflammation has been implicated with a sympathetic interference in the earlier stages of the inflammatory process and the activation of the vagal inflammatory reflex to regulate innate immune responses and cytokine functional effects in longer more chronic processes. The present chapter reviewed the overall autonomic mechanisms controlling inflammatory responses in several conditions such as, burn processes, arthritis rheumatoid, obesity, with a special focus on the inflammatory processes associated with sepsis. Furthermore, the most relevant therapeutic options for the

In summary, it is quite clear that sepsis remains a worldwide clinical challenge and therapies' outcomes depend largely on host factors. Henceforth, continuous searching for new and more effective therapies during the initial phases of sepsis is utterly important, in order to reduce

The author(s) declared no potential conflicts of interest with respect to the research, author-

1 Department of Physiology, Faculty of Medicine, Universidade de Lisboa, Portugal

3 Department of Social Pharmacy, Faculty of Pharmacy, Universidade de Lisboa, Portugal

, Isabel Rocha1,2 and Helder Mota-Filipe2,3

latter, through autonomic modulation, were also reviewed and summarized.

the mortality associated with this syndrome (condition).

shown in **Table 3**.

80 Autonomic Nervous System

**5. Conclusion**

**Conflict of interest**

**Author details**

Ângela Leal<sup>2</sup>

ship, and/or publication of this article.

\*, Mafalda Carvalho<sup>2</sup>

2 CCUL, Universidade de Lisboa, Portugal

\*Address all correspondence to: araqueleal@hotmail.com


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**Section 4**

**Autonomic Nervous System and its**

**Organization**

