SOME CARDIOVASCULAR AND AUTONOMIC EFFECTS OF FENFLURAMINE HYDROCHLORIDE

¹ Department of Pharmacology, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania

In the anesthetized rat, dog and cat, fenfluramine (0.5-10 mg/kg i.v.) produced a transient hypotensive response followed by a more dominant and prolonged hypertensive response. Pretreatment of the dog and cat with phenoxybenzamine, reserpine or cocaine eliminated the hypertensive phase. In the anesthetized cat, fenfluramine produced a contraction of the nictitating membrane which was blocked by phenoxybenzamine and reserpine. Intraventricular administration of fenfluramine to cats anesthetized with -chloralose produced a hypotensive response that was eliminated by 24-hour intraventricular pretreatment with reserpepine. Fenfluramine HCl 30 mg/kg i.p.) reduced the myocardial concentration of NE in rats by 30 to 45% at 1, 2, 4, 6 and 12 hours after administration. This reduction occurred in both the high speed supernatant and granular fractions. Gas chromatographic analysis for fenfluramine indicated that it accumulated in the supernatant and granular fractions associated with storage of NE which was not inhibited by cocaine. Preincubation of isolated guinea-pig atria with fenfluramine reduced the accumulation of He³-NE, the reduction being directly related to the concentration of fenfluramine. When fenfluramine was added to the perfusate of in situ isolated cat spleens tagged with He³-NE, there was a 50% increase in the radioactivity of the perfusate leaving the spleen. From these findings, it was concluded that fenfluramine produces its peripheral responses by releasing or displacing NE from one or more of its neuronal storage sites.