**3. Sympathetic nervous system**

4 Neuroendocrinology and Behavior

for the research.

environment.

enhancement (Tab.1.).

and shock.

function and mobilization of stem cells.

**2. The arrangement of the stress response** 

nervous system by vagus nerve and activate HPA axis (2).

peptides, the parasympathetic nervous system (acetylcholine release), changes in immune system (cytokines and other pro-inflammatory substances), mediators of endothelial

In the clinical settings, variety of interesting models and complex relations can be investigated. In particular, pathophysiology and treatment of congenital heart defects create unique models of stress response. Hypoxia, circulatory insufficiency, volume or pressure overload, hypo- or hyperthermia, pain, changes in organ perfusion, disturbances of the osmolarity, inflammatory- or immune- response create exceptional milieu and environment

In this chapter we reviewed main concepts of stress response in such environment additionally presenting some results of own research. It focuses on patients who had strong stressors working in acute or chronic manner (desaturation, increased afterload, volume overload, circulatory insufficiency) with all related elements affecting the model in clinical

The stress response is the complex process that can be initiated by immune or central nervous system. The central nervous system reacts against macroscopic threats and controls whole body response. Thus, in face of lacking of the system integrity central nervous system switches all functions over to subordinate constitutive activities to defense against the threat. The hypothalamus – pituitary – adrenal axis is activated and vasopressin, prolactin and growth hormone are released. In clinical settings corticotropin realizing hormone and vasopressin (both stimulated by adreno-cortical signals e.g. pain, fear, hypovolemia or immunologic stimuli e.g. interleukins, TNF, cytokines) (1) synergistically increase adrenocorticotropin (ACTH) secretion. ACTH induces conversion of cholesterol to cortisol which cooperates with sympathetic nervous system to prepare a body for response by mobilization of energetic substrates, increase of intravascular volume and blood pressure

The immune system reacts against microscopic threats infringing endothelial or epithelial barriers. The initial signal is amplified by cascade of lymphokines and activated cells and stimulates central stress response which eventually terminates system overstimulation. Immune response and tissue damage contribute to systemic inflammatory response syndrome (SIRS) development. These inflammatory signals are transferred to the central

Adaptation to chronic stress in humans is not well understood and unnatural situation. It is mostly created in the clinical settings when treatment of critical disease is implemented and it reaches chronic phase. After acute stress response when ACTH, prolactin, growth hormone, and thyroid hormone are elevated, the pulsatile, more physiologic pattern of neurohormones concentration appears. Although normal limits of plasma neurohormons levels in stress response are not known, inadequate concentrations can lead to acute failure Sympathetic nervous system stimulation is a part of central regulatory mechanism. It exerts many effects on the cardiovascular system by norepinephrine and epinephrine. Afferent baroreceptor signaling to the brain signals low cardiac output and efferent sympathetic pathways are activated. The main results of it are vasoconstriction (increased afterload, decreased renal perfusion), increased heart rate and contractility (increased cardiac output and wall stress), activation of RAAS. These effects are aimed on restoration of cardiac output, however, at the expense of increased myocardial oxygen demand, increased intracellular calcium toxicity, and myocardial hypertrophy. Sympathetic overstimulation can cause many undesirable effects like: expression of fetal gens, apoptosis, necrosis and remodeling and high levels of plasma norepinephrine are an independent predictor of mortality.

In clinical model of univentricular circulation characterized by increased afterload and normal saturation interesting behavioral adaptation was observed. During the exercise the heart rate at anaerobic threshold was significantly slower and patients' lung tidal volume lower compared to healthy age matched volunteers. These differences disappeared at peak effort. The effect was associated with a delayed chronotropic response of the heart and a reaction which provides a longer filling time and larger preload to the single ventricle. Delayed chronotropic response, earlier achievement of anaerobic threshold and higher value of ventilator equivalent of carbon dioxide at peak exercise obviously reflect greater impairment of cardiac output in single ventricle patients compared to healthy volunteers. The limitation of the exercise capacity is

caused mainly by abnormal autonomic nervous system activity, lower non-pulsatile pulmonary flow, neurohormonal disturbances and dysfunction of the endothelium. The primary mechanism restricting exercise capacity is the lack of ability to increase and maintain the cardiac output and pulmonary flow in response to exercise. This is complementary with delayed chronotropic reaction, decreased heart rate acceleration and abnormal reflex from ergoreceptors. Exercise studies with external pacemaker heart stimulation to increase heart rate despite of slowing it reflex did not cause increase of exercise tolerance (3). In our model heart rate was significantly lower at anaerobic threshold indicating delayed chronotropic response or adaptation to the demand of increased output generation (the slower the heart rate, the better preload). This was accompanied by significant respiratory tidal volume lowering, diminished carbon dioxide production, and respiratory equivalent of carbon dioxide compared to control group. These differences disappeared at peak exercise suggesting maintenance of optimal hemodynamic and respiratory parameters for maximal physiological effect.

Neuroendocrine Regulation of Stress Response in Clinical Models 7

and suggests etiology of such condition. Higher concentration of endothelin-1 reveals endothelial dysfunction and can contribute to higher resistance of pulmonary vascular bed and lower pulmonary blood flow at peak exercise. Higher BNP concentrations can indicate

Hypothalamic – pitutitary – adrenal system is the central stress response system linking neural regulation to neurohormonal and humoral control. In response to cortical signals e.g. fear, pain, deep emotions or immune derived factors like TNF α, Il-6 corticotropin realizing hormone, vasopressin, prolactin and growth hormone are released. Corticotropin releasing hormone stimulates sympathetic system and ACTH secretion. It reaches the adrenal cortex and stimulates cortisol production from cholesterol. Cortisol cooperates with sympathetic activation to prepare metabolism for stress response. These mechanism inhibit all growth and developmental functions, prepare metabolic substrates (glucose, fatty acids, amino

There is insufficiency of hypothalamic-pituitary-adrenal axis after pediatric cardiac surgery observed, best described as a critical illness–related corticosteroid insufficiency (CIRCI). Together with other axes derangement it is considered as one of the causes of low cardiac output syndrome in postoperative period. Many causes of this phenomenon were proposed: brain hypoperfusion, central hypothalamus and pituitary gland insufficiency, tissue resistance to adrenocorticotropic hormone (ACTH), adrenal dysfunction, cyanosis and tissues immaturities.

Endothelins (ET -1,-2,-3) are a molecules produced by endothelium acting as a vasoconstrictors and mitogenic factors. In patients with heart failure their plasma concentrations are increased their concentration is proportional to the severity of the disease. Endothelins promote vasoconstriction, inflammation, fibrosis, and hypertrophy in

Plasma ET-1 levels are elevated in patients who have cardiomyopathy or chronic heart failure, and correlate with severity and prognosis. In particular, the degree of plasma elevation of endothelin correlates with the magnitude of alterations in cardiac

In our material, higher pulmonary artery resistance was related to higher endothelin concentration in patients with single ventricle, therefore endothelin receptor antagonist

Renin angiotensin aldosterone axis exerts many effects in cardiovascular system. Neural connexion of the brain and kidneys is stimulated by low sodium, decreased perfusion,

more pronounced ventricular dysfunction (5).

**4. Hypothalamic-pituitary-adrenal axis** 

acids), increase blood pressure and intravascular volume.

**5. Endotheline** 

the pulmonary and systemic vasculature.

hemodynamics and functional class.

could result in reduction of pulmonary resistance.

**6. Renin angiotensin aldosterone axis** 


**Table 2.** Sympathetic nervous system activation

Significant positive correlation of VE/VCO2 (respiratory equivalent of carbon dioxide) at peak exercise with proBNP and endothelin-1 were found. The parameter VE/VCO2 reflects relationship between minute ventilation and carbon dioxide clearance and is considered as a more sensitive prognostic factor than oxygen consumption in diagnosis of circulatory insufficiency. In patients with chronic heart failure VE/VCO2 is increased and negatively correlated with cardiac output at peak exercise and is independent of subject effort and peripheral function (3, 4). In our study VE/VCO2 peak is significantly higher in investigated group, compared to age matched controls. The correlation with endothelin-1 and proBNP indicates the possibility of identification of such patients by neurohormonal screening tests and suggests etiology of such condition. Higher concentration of endothelin-1 reveals endothelial dysfunction and can contribute to higher resistance of pulmonary vascular bed and lower pulmonary blood flow at peak exercise. Higher BNP concentrations can indicate more pronounced ventricular dysfunction (5).
