PT - JOURNAL ARTICLE AU - Yi Zhang AU - Donald B. Hoover TI - Signaling Mechanisms for Muscarinic Receptor-Mediated Coronary Vasoconstriction in Isolated Rat Hearts DP - 2000 Apr 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 96--106 VI - 293 IP - 1 4099 - http://jpet.aspetjournals.org/content/293/1/96.short 4100 - http://jpet.aspetjournals.org/content/293/1/96.full SO - J Pharmacol Exp Ther2000 Apr 01; 293 AB - Signaling mechanisms for muscarinic receptor-mediated vasoconstriction in coronary resistance arteries were studied in potassium-arrested isolated rat hearts perfused at a constant flow rate. The cholinergic agonist bethanechol was given by bolus injection or constant infusion. Perfusion pressure was monitored as an indicator of coronary vascular resistance. Bolus injection of bethanechol evoked a phasic vasoconstriction in a dose-dependent manner, whereas infusion of bethanechol evoked a tonic vasoconstriction without producing tachyphylaxis. Bethanechol-induced phasic vasoconstriction was eliminated by perfusion with a Ca2+-free buffer. The L-type voltage-operated Ca2+ channel blocker nifedipine decreased the maximal constrictor response to bethanechol by 59 ± 2% (n = 4, P < .001), whereas the putative receptor-operated Ca2+ channel blocker SK&F 96365 converted this vasoconstriction into vasodilation that was not mediated by nitric oxide. The protein kinase C inhibitor chelerythrine reduced the maximal phasic vasoconstrictor response to bethanechol by 78 ± 2% (n = 6, P < .001) Bethanechol-induced tonic vasoconstriction was rapidly converted to a sustained vasodilation during infusion of SK&F 96365 or nifedipine, whereas infusion of chelerythrine gradually attenuated the tonic response to bethanechol. Results from other experiments do not support a role for phospholipase A2-dependent mediators in generating coronary vasoconstrictor responses to bethanechol. It is concluded that voltage-independent receptor-operated Ca2+channels, voltage-operated Ca2+ channels, and protein kinase C are major signaling components for muscarinic receptor-mediated contraction of rat coronary resistance arteries. The American Society for Pharmacology and Experimental Therapeutics