Weir, E. Kenneth, M.D.

CARDIOLOGY/VASCULAR MEDICINE AND BIOLOGY

A small percentage of patients who take the anorectic drugs fenfluramine or dexfenfluramine develop pulmonary hypertension. This pulmonary hypertension is indistinguishable clinically and pathologically from primary pulmonary hypertension, a rapid fatal condition that mainly affects young women. We have previously shown that dexfenfluramine inhibits potassium current in pulmonary artery smooth muscle cells (PASMC), depolarizes the cell membrane and causes an influx of extracellular calcium. In addition to its effect on influx of extracellular calcium, dexfenfluramine, at levels comparable to those seen in patient plasma, causes release of intracellular calcium. This might be a mechanism by which dexfenfluramine initiates pulmonary vasoconstriction and proliferation and the effect is even pronounced in the case of the major metabolite d-norfenfluramine. We have also observed that fenfluramine causes release of serotonin from the isolated perfused rat ileum. Serotonin stimulates pulmonary vasoconstriction and smooth muscle proliferation. Plasma levels of serotonin are elevated in patients with primary pulmonary hypertension.