Phorbol ester does not mimic, but antagonizes the alpha-adrenoceptor-mediated positive inotropic effect in the rabbit papillary muscle.
The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) was used to examine the hypothesis that phosphoinositide turnover is involved in the regulation of myocardial contractility mediated by stimulation of alpha-adrenoceptors in the mammalian cardiac muscle. Exposure of the isolated rabbit papillary muscle electrically driven at a rate of 1 Hz at a temperature of 37 degrees C to TPA in concentrations of 10-1000 nmol/l for 30 min did not affect the basal force of contraction. The concentration-response curve for the positive inotropic effect of (-)-phenylephrine mediated by stimulation of alpha-adrenoceptors in the presence of (+/-)-bupranolol (100 nmol/l) was shifted to the right and downward by TPA in concentrations of 30-1000 nmol/l, while the effect of (-)-phenylephrine mediated by stimulation of beta-adrenoceptors in the presence of prazosin (100 nmol/l) was not decreased, but slightly enhanced by exposure of the muscle to relatively low concentrations of TPA (10-100 nmol/l). Incubation of the membrane fraction isolated from the rabbit ventricular muscle with TPA in vitro under the same condition as employed in the physiological experiments decreased the specific binding of [3H]prazosin but not that of [3H]CGP-12177, while the non-tumor promoting phorbol ester, alpha PDD, was ineffective. These results indicate that activation of protein kinase C by TPA does not mimic the positive inotropic effect of catecholamines mediated by activation of myocardial alpha-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
D000317:Adrenergic alpha-Antagonists; D000818:Animals; D002046:Bupranolol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D010703:Phorbol Esters; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D002046:Bupranolol; D011224:Prazosin