Positive inotropic, negative chronotropic, and coronary vasoconstrictor effects of acetylcholine in isolated rat hearts: Role of muscarinic receptors, prostaglandins, protein kinase C, influx of extracellular Ca2+, intracellular Ca2+ release, and endothelium

The involvement of nitric oxide (NO), muscarinic receptors, prostaglandins, calcium influx via slow calcium channels, Ca2+ release from intracellular stores, protein kinase C, and endothelium in the positive inotropic, negati ve chronotropic, and coronary vasoconstrictor effects of acetylcholine (ACh ) has been investigated in isolated rat hearts. The perfusion of hearts wit h ACh (10(-7), 5X10(-7), and 10(-6) M) produced marked decreases in heart r ate and coronary flow and a marked increase in contractile force. Similar e ffects have been observed during the perfusion of hearts with ACh in the pr esence of N-omega-nitro-L-arginine methyl ester (L-NAME), which is an inhib itor of NO synthesis. The positive inotropic, negative chronotropic, and co ronary vasoconstrictor effects of ACh were abolished by muscarinic receptor blocker atropine. In hearts pretreated with cyclooxygenase inhibitor indom ethacin, ACh significantly decreased heart rate but did not significantly a ffect coronary flow and contractile force. In the presence of calcium chann el antagonist verapamil or protein kinase C inhibitor staurosporine, ACh pr oduced a significant drop in heart rate but did not significantly affect co ronary perfusion pressure and force of contraction. In the presence of the inhibitor of the release of Ca2+ from intracellular stores dantrolene sodiu m, ACh produced a significant increase in coronary perfusion pressure and a marked decline in heart rate, but did not significantly affect force of co ntraction, Furthermore, the disruption of endothelium by perfusing the hear ts with saponin abolished the vasoconstrictor effect of ACh but did not alt er negative chronotropic and positive inotropic effect. Our results suggest that ACh causes vasoconstrictor, negative chronotropic, and positive inotr opic effects in isolated rat hearts. Cardiac effects of ACh are related to muscarinic receptor activation, and prostaglandins modulate ACh-induced vas oconstriction and positive inotropy. Our data also suggest that protein kin ase C and calcium influx from extracellular source may be responsible for t he vasoconstrictor and positive inotropic effect of ACh. The calcium releas e from intracellular stores may mediate the positive inotropic effect, and the vasoconstrictor effect of ACh depends on an intact endothelium.