STUDIES ON THE POTENTIATION OF THE INOTROPIC ACTIONS OF CERTAIN CATECHOLAMINES BY U-0521 (3',4'-DIHYDROXY--METHYL PROPIOPHENONE)

¹ Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota

A competitive inhibitor of catechol-O-methyl transferase (COMT), 3',4'-dihydroxy--methyl propiophenone (U-0521), was found to cause a parallel shift of the dose-response curves for epinephrine and isoproterenol on isolated rabbit atria. U-0521 consistently potentiated the positive inotropic responses produced by these catecholamines although its methoxy and dimethyoxy derivatives did not. U-0521 did not potentiate responses to norepinephrine (3 x 10^-7 M). Phenylephrine, a monophenolic amine which is not a substrate for COMT, was not potentiated by U-0521. Unlike cocaine, U-0521 did not block the positive inotropic action of tyramine and potentiated that produced by isoproterenol. In the presence of U-0521, the formation of metanephrine was inhibited during the period when epinephrine produced an increase in contractile amplitude of the atrial preparations. It was concluded that the potentiating effect of U-0521 on the positive inotropic action of epinephrine and isoproterenol was due to inhibition of COMT resulting in a decreased rate of inactivation of these amines near the receptor site.