Role of muscarinic cholinergic receptors in regulation of guanosine 3':5'-cyclic monophosphate content in mammalian brain, heart muscle, and intestinal smooth muscle.

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Effects of acetylcholine and of agents that mimic or block its physiological actions have been studied upon concentrations of guanosine 3':5'-cyclic monophosphate (cyclic GMP) and adenosine 3':5'-cyclic monophosphate (cyclic AMP) in slices of mammalian cerebral cortex, heart ventricle, and ileum. Acetylcholine, and cholinomimetic agents with a predominantly muscarinic action, such as methacholine, bethanechol, and pilocarpine, induced an increase in the concentration of cyclic GMP, accompanied by no change or a slight decrease in the concentration of cyclic AMP, in all three tissues studied. Tetramethylammonium, a cholinomimetic agent with a predominantly nicotinic action, on the other hand, did not significantly alter concentrations of either cyclic GMP or cyclic AMP. The increase in the tissue content of cyclic GMP induced by acetylcholine and its muscarinic analogs was antagonized by atropine, a muscarinic blocking agent, but not by hexamethonium, a nicotinic blocking agent. These and other results suggest the generalization that the interaction of acetylcholine with muscarinic receptors, but not with nicotinic receptors, causes an increase in the concentration of cyclic GMP. The data are compatible with the hypothesis that cyclic GMP may mediate the muscarinic actions of acetylcholine. The antagonistic actions of cholinergic and adrenergic agents on the physiology of contraction of intestinal smooth muscle and of cardiac muscle are reflected in, and may result from, antagonistic actions of these compounds on the levels of both cyclic GMP and cyclic AMP in these tissues.