Influence of phorbol esters on contractile force, action potential and calcium current of isolated guinea-pig heart tissues

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Abstract
Phorbol-12,13-dibutyrate (PDB) reduced concentration-dependently the contractile force of guineapig papillary muscles (EC50 1.07 μmol/l) while phorbol-12-myristate-13-acetate (PMA) was ineffective. The protein kinase C inhibitors staurosporine (0.1 μmol/l) and polymyxin B (70 μmol/l) did not antagonize the negative inotropic effect of PDB. Neither PMA nor PDB, in concentrations up to 30 μmol/l caused significant changes of the membrane resting potential, the maximum depolarization velocity, the action potential duration or the functional refractory period in intact papillary muscles. In isolated ventricular cardiomyocytes the inward calcium current was halved by either 1 μmol/l PDB or 10 μmol/l PMA. PKC inhibitors attenuated, but could not completely abolish this effect of the phorboles. It is concluded that the negative inotropic effect of PDB is caused by a reduction of the slow inward calcium current and that this inhibition is, for the greater part, not mediated by an activation of protein kinase C.