Pharmacological Effects of Muscarinic Stimulation

CARDIOVASCULAR SYSTEM ACh has four primary effects on the cardiovascular system: vasodilation, a decrease in cardiac rate (the negative chronotropic effect), a decrease in the rate of conduction in the specialized tissues of the SA and atrioventricular (AV) nodes (the negative dromotropic effect), and a decrease in the force of cardiac contraction (the negative inotropic effect). The last effect is of lesser significance in ventricular than in atrial muscle. Certain of the above responses can be obscured by baroreceptor and other reflexes that dampen or counteract the direct responses to ACh.

Although ACh rarely is given systemically, its cardiac actions are important because of the involvement of cholinergic vagal impulses in the baroreceptor reflex and in the actions of the cardiac glycosides, antiarrhythmic agents, and many other drugs; afferent stimulation of the viscera during surgical interventions also stimulates vagal release of ACh.

The intravenous injection of a small dose of ACh produces a transient fall in blood pressure owing to generalized vasodilation, usually accompanied by reflex tachycardia. A considerably larger dose is required to elicit bradycardia or block of AV nodal conduction from a direct action of ACh on the heart. If large doses of ACh are injected after the administration of atropine, an increase in blood pressure is observed due to stimulation of nicotinic receptors on the adrenal medulla and sympathetic ganglia resulting in the release of catecholamines into the circulation and at postgan-glionic sympathetic nerve endings.

ACh produces dilation of essentially all vascular beds, including those of the pulmonary and coronary vasculature; the effect is mediated by stimulation of endothelial NO production. Vasodi-lation of coronary beds may be elicited by baroreceptor or chemoreceptor reflexes or by direct electrical stimulation of the vagus; however, neither parasympathetic vasodilator nor sympathetic vasoconstrictor tone plays a major role in the regulation of coronary blood flow relative to the effects of local oxygen tension and autoregulatory metabolic factors such as adenosine.

Dilation of vascular beds by exogenous ACh is due primarily to M3 receptors on endothelial cells. Most vessels lack cholinergic innervation, but their endothelial and smooth muscle cells express mus-carinic receptors. In each cell type, stimulation of the muscarinic receptors activates the Gq-PLC-IP3 pathway and mobilizes cell Ca2+. In endothelial cells, this leads to Ca2+-calmodulin-dependent

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