Contribution of M2 alpha and M2 beta muscarinic receptors to the action of cholinergic stimuli on prostaglandin synthesis and mechanical function in the isolated rabbit heart

N Jaiswal, G Lambrecht, E Mutschler and KU Malik

Department of Pharmacology, College of Medicine, University of Tennessee, Memphis.

This study was performed to determine the subtype of M2 muscarinic receptor that is involved in the action of cholinergic agents on prostaglandin (PG) synthesis as well as on the mechanical function of the isolated rabbit heart perfused at a constant flow rate with Krebs- Henseleit buffer. The increase in PG output elicited by acetylcholine (ACh) or arecaidine propargyl ester (APE), a selective M2 agonist was attenuated by both 11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl- 5,11-dihydro-6H- pyrido-[2,3-b][1,4]-benzodiazepine-6-one (AF-DX 116), an M2 alpha antagonist, and hexahydro-sila-difenidol (HHSiD), an M2 beta antagonist. The coronary vasodilating effect of ACh and APE was inhibited by HHSiD, but not by AF-DX 116, whereas the vasoconstrictor effect was blocked by AF-DX 116, but not by HHSiD. The decrease in heart rate produced by ACh or APE was blocked by AF-DX 116, but not by HHSiD; however, the decrease in developed tension produced by the cholinergic stimuli was abolished by all these muscarinic receptor antagonists. The increase in PG output or changes in the mechanical parameters of the heart produced by ACh or APE were not altered by adrenergic receptor antagonists, phentolamine and propranolol, or by the nicotinic receptor antagonist, hexamethonium. The effect of isoproterenol or exogenous arachidonic acid to enhance PG output was not altered by these M2 receptor antagonists; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by ACh or APE. These data indicate that the effect of cholinergic stimuli to promote cardiac PG synthesis and decrease developed tension is mediated through the activation of both M2 alpha and M2 beta subtypes of muscarinic receptors. The cholinergically induced vasodilating component of the coronary response is mediated through the activation of M2 beta, whereas the coronary vasoconstriction and the decrease in heart rate is mediated through the activation of M2 alpha muscarinic receptors.

Volume 247, Issue 1, pp. 104-113, 10/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

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