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activation of endothelial NO synthase (eNOS, NOS-3) and production of NO which diffuses to adjacent smooth muscle cells, where it stimulates the soluble guanylyl cyclase and causes relaxation (see Chapters 1 and 6). Vasodilation also may arise indirectly due to inhibition of norepinephrine (NE) release from adrenergic nerve endings by ACh. If the endothelium is damaged, as occurs under various pathophysiological conditions, the direct effect of ACh on the muscarinic receptors on vascular smooth muscle cells predominates, and the resultant mobilization of cell Ca2+ causes vasoconstriction. There is also evidence of NO-based (nitrergic) neurotransmission in peripheral blood vessels.

Cholinergic stimulation affects cardiac function both directly and by inhibiting the effects of adrenergic activation. The latter depends on the level of sympathetic drive to the heart and results in part from inhibition of cyclic AMP formation and reduction in L-type Ca2+ channel activity, mediated through M2 receptors. Inhibition of adrenergic stimulation of the heart also results from the capacity of M2 receptors to inhibit the release of NE from sympathetic nerve endings. Cholin-ergic innervation of the ventricular myocardium is less dense, and the parasympathetic fibers terminate largely on specialized conduction tissue such as the Purkinje fibers but also on some ventricular myocytes, which express M2 receptors.

In the SA node, each normal cardiac impulse is initiated by the spontaneous depolarization of the pacemaker cells (see Chapter 34). When a threshold is reached, an action potential is initiated and conducted through the atrial muscle fibers to the AV node and thence through the Purkinje system to the ventricular muscle. ACh slows the heart rate by decreasing the rate of spontaneous diastolic depolarization (the pacemaker current) and by increasing the repolarizing K+ current at the SA node (a direct effect of bg subunits of Gi/Go); in sum, the membrane potential is more negative and attainment of the threshold potential and the succeeding events in the cardiac cycle are delayed.

In atrial muscle, ACh decreases the strength of contraction. This occurs largely indirectly, as a result of decreasing cyclic AMP and Ca2+ channel activity. Direct inhibitory effects are seen at higher ACh concentrations and result from M2 receptor-mediated activation of G protein-regulated K+ channels. The rate of impulse conduction in the normal atrium is either unaffected or may increase in response to ACh, due to the activation of additional Na+ channels, possibly in response to the ACh-induced hyperpolarization. The combination of these factors is the basis for the perpetuation or exacerbation by vagal impulses of atrial flutter or fibrillation arising at an ectopic focus. In contrast, primarily in the AV node and to a much lesser extent in the Purkinje conducting system, ACh slows conduction and increases the refractory period. The decrease in AV nodal conduction usually is responsible for the complete heart block that may be observed when large quantities of cholinergic agonists are administered systemically. With an increase in vagal tone, such as is produced by digoxin, the increased refractory period can contribute to the reduction in the frequency with which aberrant atrial impulses are transmitted to the ventricle, and thus protect the ventricle during atrial flutter or fibrillation.

Although the effect is smaller than that observed in the atrium, ACh produces a negative inotropic effect in the ventricle. This inhibition is most apparent when there is concomitant adren-ergic stimulation or underlying sympathetic tone. ACh suppresses automaticity of Purkinje fibers and increases the threshold for ventricular fibrillation. To the extent that the ventricle receives cholinergic innervation, sympathetic and vagal nerve terminals lie in close proximity, and mus-carinic receptors are believed to exist at presynaptic as well as postsynaptic sites.

GASTROINTESTINAL AND URINARY TRACTS Although stimulation of vagal input to the gastrointestinal (GI) tract increases tone, amplitude of contraction, and secretory activity of the stomach and intestine, such responses are inconsistently seen with administered ACh. Poor perfusion of visceral organs and rapid hydrolysis by plasma butyrylcholinesterase limit access of sys-temically administered ACh to visceral muscarinic receptors. Parasympathetic sacral innervation causes detrusor muscle contraction, increased voiding pressure, and ureter peristalsis, but for similar reasons these responses are not evident with administered ACh.

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