SELECTIVE-INHIBITION BY PHORBOL 12,13-DIBUTYRATE OF THE ALPHA(1)-RECEPTOR-MEDIATED POSITIVE INOTROPIC EFFECT

Influence of the protein kinase C activator phorbol 12,13-dibutyrate on the alpha1- and beta-adrenoceptor-mediated positive inotropic effect was studied in the rabbit ventricular myocardium. Phorbol 12,13-dibutyrate (10(-8)-10(-6) M) inhibited the positive inotropic effect mediated by alpha1-adrenoceptors in a concentration-dependent manner, while the positive inotropy mediated by beta-adrenoceptors was not affected by phorbol 12,13-dibutyrate up to 3 x 10(-7) M. Phorbol 12,13-dibutyrate at 10(-6) M decreased the beta-mediated effect, but.the extent of inhibition was less than that of alpha1-mediated effect produced by 10(-8) M phorbol 12,13-dibutyrate. Thus, the inhibition induced by phorbol 12,13-dibutyrate was 100-fold more selective for alpha1- than for beta-mediated inotropy. Phorbol 12,13-dibutyrate at 10(-7) M increased the basal force of contraction in some preparations, but decreased it at 3 x 10(-7) M and higher in a concentration-dependent manner. In membrane fractions derived from the rabbit ventricular muscle, phorbol 12,13-dibutyrate did not affect the specific binding of [H-3]prazosin. A nonhydrolyzable GTP analogue GTP(gamma)S shifted the epinephrine-induced displacement curve of [H-3]prazosin to the right, but phorbol 12,13-dibutyrate did not affect the curve. Accumulation of [H-3]inositol monophosphate induced by alpha1 stimulation was inhibited by phorbol 12,13-dibutyrate. These findings indicate that phorbol 12,13-dibutyrate may induce the selective uncoupling of the myocardial alpha1-receptor stimulation to activation of phospholipase C, and inhibit selectively the alpha1-mediated positive inotropy.