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 alpha1- 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 muM) selectively attenuated the PIE mediated by al-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 [H-3]prazosin binding at the concentrations that elicited the functional modulation. Accumulation of [H-3]inositol monophosphate (IP1) induced by alpha1-adrenoceptor stimulation was not affected by the PKC inhibitors. Phorbol 12,13-dibutyrate (PDBu), a PKC activator, also selectively attenuated the alpha1-mediated PIE, but in association with the inhibition of the alpha1-mediated IP1 accumulation. Staurosporine (1 nM), but not H-7, antagonized the PDBu-induced inhibitory action on the alpha1-mediated PIE. These findings indicate that staurosporine, NA 0345 and H-7 produce a selective inhibition of the alpha1-mediated PIE, probably through inhibition of the alpha1-adrenoceptor-mediated activation of PKC. On the contrary, externally administered phorbol ester may act by uncoupling of alpha1-adrenoceptors to activation of phospholipase C through a pathway different from endogenous diacylglycerol to lead to a selective inhibition of the alpha1-mediated PIE.