Low doses of muscarinic agonists given intravenously relax arterial smooth muscle and produce a fall in blood pressure. These responses result from the stimulation of muscarinic receptors on vascular endothelial cells (Fig. 12.2). Activation of these receptors causes the endothe-lial cells to synthesize and release nitric oxide. Nitric oxide can diffuse into neighboring vascular smooth muscle cells, where it activates soluble guanylyl cyclase, thereby increasing the synthesis of cyclic guanosine monophosphate (cGMP) and relaxing the muscle fibers. Most of the resistance vasculature is not innervated by choliner-gic neurons, and the physiological function of the en-dothelial muscarinic receptors is not known. However, activation of these receptors by directly acting choli-nomimetic drugs has major pharmacological significance, as the potentially dangerous hypotension produced by their activation is an important limitation to the systemic administration of muscarinic agonists.
Although the release of ACh onto the heart by the vagus nerve slows the heart rate, a low dose of a mus-carinic agonist can sometimes increase the heart rate. This paradoxical effect is produced when the decrease in blood pressure produced by stimulation of endothe-lial muscarinic receptors, as described earlier, triggers the activation of a compensatory sympathetic reflex stimulation of the heart. Sympathetic stimulation increases heart rate and vasomotor tone, partially counteracting the direct vasodilator response. Therefore, the tachycardia produced by muscarinic agonists is indirect. At higher concentrations of a muscarinic agonist, the direct effects on cardiac muscarinic (M2) receptors in the
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