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Endogenous nitric oxide signalling system and the cardiac muscarinic acetylcholine receptor‐inotropic response
Author(s) -
SterinBorda Leonor,
Echagüe Agustina Vila,
Leiros Claudia Perez,
Genaro Ana,
Borda Enri
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb16646.x
Subject(s) - muscarinic acetylcholine receptor , acetylcholine , nitric oxide , inotrope , muscarinic acetylcholine receptor m3 , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m4 , pharmacology , atropine , medicine , muscarinic acetylcholine receptor m5 , chemistry , endogeny , endocrinology , receptor
1 In this paper we have determined the different signalling pathways involved in muscarinic acetylcholine receptor (AChR)‐dependent inhibition 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 and increased production of cyclic GMP. 3 Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase, shifted the dose‐response curve of carbachol on contractility to the right. These inhibitors also attenuated the muscarinic receptor‐dependent increase in cyclic GMP and activation of nitric oxide synthase. In addition, sodium nitroprusside, isosorbide, or 8‐bromo cyclic GMP, induced a negative inotropic effect, increased cyclic GMP and activated nitric oxide synthase. 4 These results suggest that carbachol activation of M 2 AChRs, exerts a negative inotropic effect associated with increased production of nitric oxide and cyclic GMP. The mechanism appears to occur secondarily to stimulation of phosphoinositides turnover via phospholipase C activation. This in turn, triggers cascade reactions involving calcium/calmodulin and protein kinase C, leading to activation of nitric oxide synthase and soluble guanylate cyclase.