Protein kinase C is not involved in alpha 1-adrenoceptor-mediated positive inotropic effect

This study was performed to determine whether activation of protein kinase C is responsible for the positive inotropic effect of alpha 1-adrenoceptor stimulation in rat papillary muscle. In the presence of 1 microM propranolol, phenylephrine (10 microM) produced triphasic inotropic response that was accompanied by prolongation of action potential duration (APD) and hyperpolarization of membrane potential. Phorbol 12,13-dibutyrate (PDBu, 0.1 microM) abolished the negative inotropic effect of phenylephrine and apparently resulted in enhancement of the positive inotropic effect. PDBu also attenuated the phenylephrine-induced hyperpolarization without affecting the APD prolongation. However, such changes were not observed with 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.1 microM). Neither PDBu nor TPA increased the force of contraction or prolonged APD similar to phenylephrine. The protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H 7, 10 microM) did not suppress the changes induced by PDBu, and more importantly H 7 did not affect the inotropic and electrophysiological effects of phenylephrine. Both TPA and PDBu significantly inhibited the phenylephrine-induced phosphoinositide hydrolysis as measured by [3H]inositol monophosphate, and these inhibitory effects were eliminated in the presence of H 7. Our results provide an argument against a role of protein kinase C activation in the alpha 1-adrenoceptor-mediated inotropic and electrophysiological effects.