Role of Muscarinic Cholinergic Receptors in Regulation of Guanosine 3′:5′-Cyclic Monophosphate Content in Mammalian Brain, Heart Muscle, and Intestinal Smooth Muscle

Abstract

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 acetyicholine.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.A substantial amount of evidence now exists indicating that several hormones and neurotransmitter agents may exert their biological actions by altering the amount of adenosine 3':5'-monophosphate (cyclic AMP) in target cells. In recent years, the possibility has been raised that guanosine 3':5'-cyclic monophosphate (cyclic GMP) may also play a significant role in the regulation of metabolism and function in animal tissues. Cyclic GMP has been found in tissues and fluids of several species (e.g., 1-4), and enzymes have been found that catalyze the synthesis (4, 5) and breakdown (6) of cyclic GMP. In addition, a family of protein kinases has been found that is specifically activated by cyclic GMP (7-9), rather than by cyclic AMP, and it has been proposed (7) that the biological effects of cyclic GMP are mediated through this family of protein kinases (7-9). Nevertheless, little is known about the factors that regulate the concentration of cyclic GMP in tissues or about the nature of the biological effects that may be regulated by cyclic GMP.Recent studies indicate that acetylcholine can cause the accumulation of cyclic GMP in heart (10, 11), brain (11, 12), and ductus deferens (13). Perfusion of isolated rat heart with acetylcholine caused an increase of up to 140% in cyclic GMP content (10). Moreover, application of low concentrations of acetylcholine to slices of rat heart caused increases of up to 10-fold in the concentration of cyclic ...

Relationship Between the Levels of Intracellular Cyclic Nucleotides and Mechanical Responses Induced by Drugs

“…It has also been reported that acetylcholine and other muscarinic receptor stimulants increase the intracellular level of cyclic GMP in mammalian heart muscle, brain, lung slices and intestinal smooth muscle (2,7,8,9,10,11). Recently, Murad and Kimura (12) tested the effects of several drugs on cyclic AMP and cyclic GMP levels in incubations of guinea pig tracheal ring preparations and concluded that drugs which can relax the tracheal muscle increased the cyclic AMP level and drugs which can contract the muscle increased the cyclic GMP level.…”

“…Several authors have reported that elevation of the intracellular cyclic AMP level is associated with relaxation of smooth muscle induced by isoprenaline or papaverine (1,2,3,4,5,6). It has also been reported that acetylcholine and other muscarinic receptor stimulants increase the intracellular level of cyclic GMP in mammalian heart muscle, brain, lung slices and intestinal smooth muscle (2,7,8,9,10,11).…”

Effect of isoproterenol and forskolin on amylase release from parotid tissue after chronic pilocarpine administration in rats following ligation removal.

“…Pilocarpine induces an increase in the concentration of cyclic GMP (14). Increase of cyclic GMP levels appears to require calcium.…”

Changes in cyclic AMP and cyclic GMP levels in the contraction-relaxation cycle of isolated smooth muscle cells from guinea-pig taenia caeci.

“…There are many reports suggesting that cyclic AMP is closely associated with the smooth muscle relaxation (Bowman et al, 1970;Andersson et al, 1972;Honeyman et al, 1978;Scheid et al, 1979). On the other hand, acetylcholine and other muscarinic agonist cause the contraction of intestinal smooth muscle and increase the cyclic GMP level (Lee et al, 1972). And yet, some have reported that intracellular cyclic GMP elevation is associated with smooth muscle relaxation (Napori et al, 1980;Gruetter et al, 1981).…”

“…On the other hand, since Lee et al(1972) suggested that cholinergic effect was associated with an increased concentration of cyclic GMP in intestinal smooth muscle, the role of cyclic GMP in the regulation of the contraction-relaxation cycle in the smooth muscle has also been investigated. Despite Recently, Honeyman et al(1978) and Scheid et al(1979) reported the role of cyclic AMP in smooth muscle relaxation making use of isolated smooth muscle cells from the stomach of an amphibian.…”