Endogenous nitric oxide signalling system and the cardiac muscarinic acetylcholine receptor-inotropic response.
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 M2 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 M2 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.
Sterin-Borda
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L
Centro de Estudios Farmacológicos y de Botánica (CEFYBO), Consejo Nacional de Investigaciones Cientificas y Técnicas de la República Argentina (CONICET), Buenos Aires, Argentina.
Echagüe
A V
AV
Leiros
C P
CP
Genaro
A
A
Borda
E
E
D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001665:Binding Sites; D002217:Carbachol / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D010276:Parasympatholytics; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D010890:Pirenzepine; D001285:Atropine; D002217:Carbachol; D019001:Nitric Oxide Synthase; D010738:Type C Phospholipases; D006152:Cyclic GMP; C048593:otenzepad