Inotropic effects of staurosporine, NA 0345 and H-7, protein kinase C inhibitors, on rabbit ventricular myocardium: selective inhibition of the positive inotropic effect mediated by alpha 1-adrenoceptors.
The influence of protein kinase C (PKC) inhibitors, staurosporine, NA 0345 and H-7, on the alpha 1- and beta-adrenoceptor-mediated positive inotropic effect (PIE) was studied in rabbit ventricular myocardium. Staurosporine (1-10 nM), NA 0345 (10-100 nM) and H-7 (1-10 microM) selectively attenuated the PIE mediated by alpha 1-adrenoceptors at concentrations that did not affect the beta-mediated PIE and basal force of contraction. Staurosporine at higher concentrations (> 10 nM) decreased the basal force, while NA 0345 and H-7 did not. In membrane fractions derived from rabbit ventricular muscle, neither staurosporine, NA 0345 nor H-7 modified the specific [3H]prazosin binding at the concentrations that elicited the functional modulation. Accumulation of [3H]inositol monophosphate (IP1) induced by alpha 1-adrenoceptor stimulation was not affected by the PKC inhibitors. Phorbol 12,13-dibutyrate (PDBu), a PKC activator, also selectively attenuated the alpha 1-mediated PIE, but in association with the inhibition of the alpha 1-mediated IP1 accumulation. Staurosporine (1 nM), but not H-7, antagonized the PDBu-induced inhibitory action on the alpha 1-mediated PIE. These findings indicate that staurosporine, NA 0345 and H-7 produce a selective inhibition of the alpha 1-mediated PIE, probably through inhibition of the alpha 1-adrenoceptor-mediated activation of PKC. On the contrary, externally administered phorbol ester may act by uncoupling of alpha 1-adrenoceptors to activation of phospholipase C through a pathway different from endogenous diacylglycerol to lead to a selective inhibition of the alpha 1-mediated PIE.
Endoh
M
M
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Norota
I
I
Takanashi
M
M
Kasai
H
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D007211:Indoles; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D019311:Staurosporine
D000470:Alkaloids; D002227:Carbazoles; D007211:Indoles; D007546:Isoquinolines; D010716:Phosphatidylinositols; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; C059550:NA 0345; D015240:Phorbol 12,13-Dibutyrate; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine; D011224:Prazosin