INTERACTIONS BETWEEN POTENTIATING AGENTS OF ADRENERGIC AMINES IN RABBIT AORTIC STRIPS

¹ Department of Pharmacology, Downstate Medical Center, State University of New York, Brooklyn, New York

The cateehol-O-methyltransferase (COMT) inhibitor, 4-tropolone acetamide (4-TA), increases the contractile response of rabbit aortic strips to norepinephrine (NE), epinephrine and a-methyl-NE. Since 4-TA did not alter the responses to the non-catechols phenylephnine and synephrine, the potentiation of catecholamines probably results from inhibition of COMT. Cocaine potentiated the effects of all these sympathomimetics to varying degrees. The effects of 4-TA were the same in control aortic strips and in strips pretreated with cocaine. Likewise, the effects of cocaine were the same in control and 4-TA-pretreated strips. This suggests that the rates of O-methylation and of neuronal uptake are largely independent of one another in vascular tissue. Desipramine, tripelennamine, ouabain, pronethalol, bretylium and guanethidine all decreased the potentiation of NE produced by cocaine, probably by blocking the neuronal uptake mechanism. Bretylium, guanethidine, hydrocortisone and GD 131 all decreased the potentiation of NE produced by 4-TA. These drugs probably decrease NE O-methylation either by 1) inhibiting COMT, 2) decreasing the availability of S-adenosylmethionine or 3) blocking the access of NE to extraneuronal COMT. Inhibition of monoamine oxidase increased the potentiating effect of 4-TA. This is consistent with the hypothesis that monoamine oxidase and COMT metabolize NE from the same extraneuronal pool in the tissue. A diagrammatic model is presented which illustrates the relationships between the various mechanisms for NE inactivation in vascular tissue.