Kan H, Ruan Y, Malik K U
Department of Pharmacology, College of Medicine, University of Tennessee Center for the Health Sciences, Memphis, USA.
J Pharmacol Exp Ther. 1996 Mar;276(3):934-41.
The present study was conducted to localize and characterize the subtype(s) of muscarinic receptor involved in prostacyclin production elicited by the cholinergic transmitter acetylcholine (ACh) in various cell types in the rabbit heart. ACh increased prostacyclin synthesis, measured as 6-keto-prostaglandin(1 alpha) (6-keto-PGF(1 alpha)), in cultured coronary endothelial cells and freshly dissociated ventricular myocytes in a dose-dependent manner, but not in cultured coronary smooth muscle cells of rabbit heart. McN-A-343 {(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride}, a selective M1 muscarinic ACh receptor (mAChR) agonist, did not alter 6-keto-PGF(1 alpha) synthesis in these cell types. ACh induced 6-keto-PGF(1 alpha) synthesis in coronary endothelial cells and ventricular myocytes was not altered by a low concentration (0.01 microM) of pirenzepine, an M1 mAChR antagonist, but was reduced by a higher concentration (1 microM). In coronary endothelial cells, ACh-induced 6-keto-PGF(1 alpha) production was reduced by hexahydrosila-difendial (HHSiD), an M3 mAChR antagonist, and in ventricular myocytes by both AF-DX 116 [11-{2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H- pyrido[2,3-b]-benzodiazepine-6 one}], an M2 receptor antagonist, and HHSiD. The decrease by ACh of isoproterenol-stimulated cAMP accumulation was minimized by AF-DX 116, but not by HHSiD or pirenzepine. Pertussis toxin treatment minimized ACh-induced decrease in isoproterenol-stimulated rise in cAMP, but not ACh-induced 6-keto-PGF(1 alpha) synthesis. These data suggest that ACh stimulates prostacyclin production in coronary endothelial cells via M3 mAChR and in ventricular myocytes via M2 and M3 mAChR, and may contribute to its cardioprotective effects. Moreover, ACh induced decrease in cAMP, but not the increase in 6-keto-PGF (1 alpha) production, is mediated by pertussis toxin-sensitive G(alpha i) proteins in these cells.
