EFFECT OF DEXFENFLURAMINE TREATMENT IN RATS EXPOSED TO ACUTE AND CHRONIC HYPOXIA

The anorexiant dexfenfluramine, which inhibits 5-hydroxytryptamine (5- HT) uptake, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. The aim of this study wa s to investigate in rats whether dexfenfluramine (1) alters the pulmon ary vasomotor effects of 5-HT and (2) aggravates the development of pu lmonary hypertension during exposure to various levels of chronic hypo xia. In isolated lungs from normoxic rats, dexfenfluramine up to 10(-4 ) M did not elicit any vasoactive effects, and neither did pretreatmen t with dexfenfluramine (10(-5) M in the perfusate) modify the vasoacti ve effects of 5-HT. In normoxic conscious rats, dexfenfluramine given intravenously potentiated the pulmonary presser response to acute hypo xia (10% O-2) In rats chronically treated with dexfenfluramine during a 2-wk exposure to 15% or 10% O-2, plasma 5-HT concentrations were sig nificantly increased compared with hypoxic controls, whereas no differ ences were found for pulmonary artery pressure, right ventricular hype rtrophy, or pulmonary vessel muscularization. In contrast, a continuou s 5-HT infusion providing a sustained increase in plasma 5-HT levels w as associated with increased muscularization of distal pulmonary arter ies in response to 10% O-2. Simultaneous administration of dexfenflura mine prevented the effect of exogenous 5-HT on vascular remodeling. Ou r findings show that dexfenfluramine does not potentiate the developme nt of pulmonary hypertension in rats exposed to chronic hypoxia, despi te its effect on plasma 5-HT concentrations.