PHORBOL-12,13-DIBUTYRATE ANTAGONIZES THE ALPHA-1-ADRENOCEPTOR-MEDIATED POSITIVE INOTROPIC EFFECT IN THE RABBIT VENTRICULAR MYOCARDIUM

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. 1990 The British Pharmacological Society