ENDOGENOUS NITRIC-OXIDE SIGNALING SYSTEM AND THE CARDIAC MUSCARINIC ACETYLCHOLINE RECEPTOR-INOTROPIC RESPONSE

1 In this paper we have determined the different signalling pathways i nvolved in muscarinic acetylcholine receptor (AChR)-dependent inhibiti on of contractility in rat isolated atria. 2 Carbachol stimulation of M(2) muscarinic AChRs exerts a negative inotropic response, activation of phosphoinositide turnover, stimulation of nitric oxide synthase an d increased production of cyclic GMP. 3 Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guany late cyclase, shifted the dose-response curve of carbachol on contract ility to the right. These inhibitors also attenuated the muscarinic re ceptor-dependent increase in cyclic GMP and activation of nitric oxide synthase. In addition, sodium nitroprusside, isosorbide, or 8-bromo c yclic GMP, induced a negative inotropic effect, increased cyclic GMP a nd activated nitric oxide synthase. 4 These results suggest that carba chol activation of M(2) AChRs, exerts a negative inotropic effect asso ciated with increased production of nitric oxide and cyclic GMP. The m echanism appears to occur secondarily to stimulation of phosphoinositi des turnover via phospholipase C activation. This in turn, triggers ca scade reactions involving calcium/calmodulin and protein kinase C, lea ding to activation of nitric oxide synthase and soluble guanylate cycl ase.