Phorbol-12,13-dibutyrate antagonizes the alpha 1-adrenoceptor-mediated positive inotropic effect in the rabbit...

The phorbol ester phorbol-12,13-dibutyrate (PDBu) elicited a slight but significant positive inotropic effect (PIE) (10-100 nM) in the presence of a beta-adrenoceptor antagonist (+/-)-bupranolol (300 nM). PDBu (10-1000 nM) inhibited the alpha 1-adrenoceptor mediated PIE in a concentration-dependent manner, while beta-adrenoceptor-mediated PIE was not decreased by PDBu up to 300 nM. Thus, PDBu exerted a differential effect on alpha- and beta-adrenoceptor-mediated PIE, and was much more effective than 12-O-tetradecanoylphorbol-13-acetate (TPA) in antagonizing the alpha-adrenoceptor-mediated PIE. These findings imply that (1) certain subcellular process of myocardial alpha-adrenoceptor stimulation may be specifically antagonized by an activation of protein kinase C induced by PDBu or TPA; (2) there may be species difference in the response to activation of protein kinase C, which results in differential modulation of myocardial alpha 1-adrenoceptor-mediated regulation of contractility among different mammalian species.