Am. J. Respir. Crit. Care Med., Volume 158, Number 4, October 1998, 1061-1067

Nitric Oxide Deficiency in Fenfluramine- and Dexfenfluramine-induced Pulmonary Hypertension

STEPHEN L. ARCHER, KHIER DJABALLAH, MARC HUMBERT, E. KENNETH WEIR, MURIEL FARTOUKH, JOSETTE DALL'AVA-SANTUCCI, JEAN-CHRISTOPHE MERCIER, GERALD SIMONNEAU, and A. TUAN DINH-XUAN

Cardiology Division, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine (Cardiology), Veterans Affairs Medical Center, and University of Minnesota, Minneapolis, Minnesota; Hopital Cochin, Departement de Physiologie Respiratoire, and Hopital Robert Debré, Service de Réanimation Pediatrique, Paris; and Service des Maladies Vasculaires Pulmonaires, Hôpital Antoine-Béclère, Clamart, France

Dexfenfluramine and fenfluramine greatly increase the risk of developing pulmonary hypertension (PHT). The mechanism of anorexigen-associated PHT (AA-PHT) and the reason PHT occurs in a minority of people exposed are unknown. Anorexigens are weak pulmonary vasoconstrictors, but they become potent when synthesis of the endogenous vasodilator nitric oxide (NO) is suppressed. We hypothesized NO deficiency predisposes affected individuals to develop AA-PHT. A prospective, case-control, study was performed on consecutive patients with AA-PHT (n = 9). Two sex-matched control groups were selected: patients with primary PHT (P-PHT, n = 8) and normal volunteers (n = 12). Lung NO production (VNO) and systemic plasma oxidation products of NO (NOx) were measured at rest and during exercise. AA-PHT developed 17 ± 6 mo after a short course of anorexigen (6 ± 2 mo) and was irreversible. VNO was lower in AA-PHT than in P-PHT and correlated inversely with PVR (p < 0.05). The apparent VNO deficiency may have resulted from increased oxidative inactivation of NO in patients with AA-PHT, as their NOx levels were elevated (p < 0.05) in inverse proportion to VNO (r² = 0.55; p < 0.02). In susceptible persons, anorexigens can cause an irreversible syndrome of PHT, hypoxemia, and systemic vascular complications after brief exposures. These patients have a relative NO deficiency years after discontinuing the anorexigen, perhaps explaining their original susceptibility.

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