THE MECHANISM OF THE POTENTIATION OF NOREPINEPHRINE BY ANTIHISTAMINICS

¹ Department of Pharmacology, University of Texas Southwestern Medical School, Dallas, Texas

Blood pressure responses to graded doses of l-norepinephrine were measured in rats before and after tripelennamine, d-chlorpheniramine, phenindamine, pyrilamine, promethazine and cocaine. Tripelennamine, d-chlorpheniramine and cocaine augmented the pressor response to norepinephrine; these compounds and phenindamine increased the duration of this pressor response. Chronotropic response to and uptake of tritiated dl-norepinephrine (dl-NE) were determined simultaneously in in vitro experiments with these drugs and the antihistamine diphenhydramine. Tripelennamine, diphenhydramine and cocaine reduced uptake while increasing the chronotropic response to added tritiated norepinephrine (H³-NE). d-Chlorpheniramine and phenindamine reduced uptake but did not affect the response to a single addition of H³-NE. However, experiments with cumulative doses of dl-NE before and after the addition of d-chlorpheniramine or phenindamine demonstrated that d-chlorpheniramine increased the sensitivity of rat atria to norepinephrine while phenindamine did not. Increased chronotropic response to norepinephrine by cocaine was not changed in the presence of phenindamine; tripelennamine or phenindamine did not alter the chronotropic response to dl-isoproterenol. These experiments suggest that interaction of adrenergic receptors with antihistamine did not occur. The findings are consistent with the thesis that inhibition of amine uptake at the neuronal membrane may lead to an increased amine accumulation in the vicinity of the receptor, which results in a potentiated response.

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