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 alpha 1- 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 alpha 1-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 alpha 1-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 alpha 1- 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 [3H]prazosin. A nonhydrolyzable GTP analogue GTP gamma S shifted the epinephrine-induced displacement curve of [3H]prazosin to the right, but phorbol 12,13-dibutyrate did not affect the curve. Accumulation of [3H]inositol monophosphate induced by alpha 1 stimulation was inhibited by phorbol 12,13-dibutyrate. These findings indicate that phorbol 12,13-dibutyrate may induce the selective uncoupling of the myocardial alpha 1-receptor stimulation to activation of phospholipase C, and inhibit selectively the alpha 1-mediated positive inotropy.
Endoh
M
M
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Otomo
J
J
Norota
I
I
Takanashi
M
M
D000818:Animals; D002046:Bupranolol / Q000494:pharmacology; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D006868:Hydrolysis; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011224:Prazosin / Q000493:pharmacokinetics; D011817:Rabbits; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D016278:Ventricular Function, Right / Q000187:drug effects* / Q000502:physiology
D010716:Phosphatidylinositols; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D015240:Phorbol 12,13-Dibutyrate; D002046:Bupranolol; D011224:Prazosin