ANOREXIC AGENTS AMINOREX, FENFLURAMINE, AND DEXFENFLURAMINE INHIBIT POTASSIUM CURRENT IN RAT PULMONARY VASCULAR SMOOTH-MUSCLE AND CAUSE PULMONARY VASOCONSTRICTION

Background The appetite suppressant aminorex fumarate is thought to ha ve caused an epidemic of pulmonary hypertension in Europe in the 1960s . More recently, pulmonary hypertension has been described in some pat ients taking other amphetamine-like, anorexic agents: fenfluramine and its d-isomer, dexfenfluramine. No mechanism has been demonstrated tha t might account for the association between anorexic drugs and pulmona ry hypertension. Methods and Results Using the whole-cell, patch-clamp technique. we found that aminorex, fenfluramine, and dexfen-fluramine inhibit potassium current in smooth muscle cells taken from the small resistance pulmonary arteries of the rat lung. Dexfenfluramine causes reversible membrane depolarization in these cells. These actions an s imilar to those of hypoxia, which initiates pulmonary vasoconstriction by inhibiting a potassium current in pulmonary vascular smooth muscle . In the isolated, per fused rat lung, aminorex, fenfluramine, and dex fenfluramine induce a dose-related increase in perfusion pressure. Whe n the production of endogenous NO is inhibited by N-nitro-L-arginine m ethyl ester, the presser response to dexfenfluramine is greatly enhanc ed. Conclusions These observations indicate that anorexic agents, like hypoxia, can inhibit potassium current, cause membrane depolarization , and stimulate pulmonary vasoconstriction. They suggest one mechanism that could be responsible for initiating pulmonary hypertension in su sceptible individuals. It is possible that susceptibility is the resul t of the reduced production of an endogenous vasodilator, such as NO, but this remains speculative.