**2. Influence of acetylcholine on chronic diseases**

Acetylcholine, being a mediator of cell to cell communication, and responsible for various peripheral and non-neuronal cholinergic signals. Any alteration in the levels of acetylcholine leads to chronic diseases. The same has been depicted in **Figure 1**.

*Role of Acetylcholine in Chronic Diseases DOI: http://dx.doi.org/10.5772/intechopen.110663*

**Figure 1.**

*The graphical illustration of acetylcholine effect on chronic disorders.*

#### **2.1 Acetylcholine and cardiovascular system**

The heart's purpose is to pump blood to body tissues and organs. Myocardial infarction, being an index event, causes anatomical and physiological changes in the heart, called "cardiac remodeling". These alterations have been seen only at molecular and cellular stages in the cardiomyocyte. Based on the extent of the damage, cardiac remodeling may escalate to heart failure and, eventually, death [11]. Despite significant efforts in understanding the components implicated in how heart failure evolves, the mode of action underlying the phenomenon remains unknown.

ACh is secreted in the heart vie para-sympathetic division of the ANS and frequently serves in offsetting the effects of fight/flight system. A highly innervated heart's atrial valve activates cholinergic system that reduces heart rate, atrioventricular contractility, and node conduction velocities. Although ventricles displayed cholinergic fibers, however their density within ventricles remain substantially lower than in the atrium [12].

ACh has been universally considered as the primary neurotransmitter of parasympathetic nervous system since the Otto Loewi experimental times till present day investigations. The processes involved in its production and release have now been thoroughly elucidated. The operations of choline acetyltransferase (ChAT), which converts acetyl-CoA and choline into ACh in the cytoplasm, are required for ACh synthesis. The vesicular ACh transporter (VAChT) stores cytoplasmic ACh in synaptic vesicles, hence the level of ACh discharged is directly related to the quantity of VAChT. Increased expression of VAChT leads to increased ACh release, whereas decreased VAChT expression leads to decreased ACh release. Ca2+ promotes the exocytosis of ACh-filled vesicles by stimulating vesicle fusion with the biological membranes, permitting ACh to be released into the extracellular environment [13].

ACh, being liberated into the extracellular environment, can adhere to nicotinic (nAChR) or muscarinic (mAChR) receptors, activating particular signal transduction series in various types of cells. The muscarinic receptor, a G proteincoupled receptor, is the most important ACh receptor in the heart. The subtypes of Muscarinic receptors (M1–M5) seem to be present all across the systemic circulation and have a range of physiological roles. The most frequent heart's muscarinic receptor subtype is type 2 i.e., AChR-M2). The G-inhibitory (Gi) protein is connected to AChR-M2, whose expression has been thought to counterbalance adrenaline activation via the G-stimulatory (Gs) protein. Cholinesterases, found in the extracellular environment, are present numerously in the heart, break ACh molecules quickly. Incredibly little quantity of ACh persist in the extracellular environment, eliminating the actions of non-receptor-mediated signals. The high-affinity choline transporter transports the choline produced by ACh breakdown again to the cytoplasm of the cell (CHT 1). Considering the fact that ACh-synthesizing cells require choline from the extracellular environment in order to synthesize ACh, CHT1 activity is a step-limiting element in ACh production. The ACh release by heart myocytes reliant on the activity of VAChT. This premise is supported by three pieces of evidence. First, vesicle-like structures were identified to present together in accompany of VAChT in cardiac myocytes. Secondly, knocked out VAChT derived heart myocytes from mice have decreased Ach secretion. Third, ACh was found in the supernatant of in vitro cardiomyocyte preparations, however absent in VAChT mutant animals (cardiac specific) [14].
