H. Kan et al., LOCALIZATION AND CHARACTERIZATION OF THE SUBTYPE(S) OF MUSCARINIC RECEPTOR INVOLVED IN PROSTACYCLIN SYNTHESIS IN RABBIT HEART, The Journal of pharmacology and experimental therapeutics, 276(3), 1996, pp. 934-941
The present study was conducted to localize and characterize the subty
pe(s) of muscarinic receptor involved in prostacyclin production elici
ted by the cholinergic transmitter acetylcholine (ACh) in various cell
types in the rabbit heart. ACh increased prostacyclin synthesis, meas
ured as 6-keto-prostaglandin(1 alpha) (6-keto-PGF(1 alpha)), in cultur
ed coronary endothelial cells and freshly dissociated ventricular myoc
ytes in a dose-dependent manner, but not in cultured coronary smooth m
uscle cells of rabbit heart. McN-A-343 2-butyny1)-1-trimethylammonium-
m-chlorocarbanilate chloride}, a selective M(1) muscarinic ACh recepto
r (mAChR) agonist, did not alter 6-keto-PGF(1 alpha) synthesis in thes
e cell types. ACh induced 6-keto-PGF(1 alpha) synthesis in coronary en
dothelial cells and ventricular myocytes was not altered by a low conc
entration (0.01 mu M) of pirenzepine, an M(1) mAChR antagonist, but wa
s reduced by a higher concentration (1 mu M). In coronary endothelial
cells, ACh-induced 6-keto-PGF(1 alpha) production was reduced by hexah
ydro-sila-difendial (HHSiD), an M(3) mAChR antagonist, and in ventricu
lar myocytes by both AF-DX 116 -dihydro-6H-pyrido-[2,3-b]-benzodiazepi
ne-6-one}], an M(2) receptor antagonist, and HHSiD. The decrease by AC
h of isoproterenol-stimulated cAMP accumulation was minimized by AF-DX
116, but not by HHSID or pirenzepine. Pertussis toxin treatment minim
ized ACh-induced decrease in isoproterenol-stimulated rise in cAMP, bu
t not ACh-induced 6-keto-PGF(1 alpha) synthesis. These data suggest th
at ACh stimulates prostacyclin production in coronary endothelial cell
s via M(3) mAChR and in ventricular myocytes via M(2) and M(3) mAChR,
and may contribute to its cardiprotective effects. Moreover, ACh induc
ed decrease in cAMP, but not the increase in 6-keto-PGF(1 alpha) produ
ction, is mediated by pertussis toxin-sensitive G(alpha i) proteins in
these cells.