NITRIC-OXIDE DEFICIENCY IN FENFLURAMINE-INDUCED PULMONARY-HYPERTENSION AND DEXFENFLURAMINE-INDUCED PULMONARY-HYPERTENSION

Dexfenfluramine and fenfluramine greatly increase the risk of developi ng pulmonary hypertension (PHT). The mechanism of anorexigen-associate d PHT (AA-PHT) and the reason PHT occurs in a minority of people expos ed are unknown. Anorexigens are weak pulmonary vasoconstrictors, but t hey become potent when synthesis of the endogenous vasodilator nitric oxide (NO) is suppressed. We hypothesized NO deficiency predisposes af fected individuals to develop AA-PHT. A prospective, case-control, stu dy 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 a nd 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-P HT than in P-PHT and correlated inversely with PVR (p < 0.05). The app arent VNO deficiency may have resulted from increased oxidative inacti vation of NO in patients with AA-PHT, as their NOx levels were elevate d (p < 0.05) in inverse proportion to VNO (r(2) = 0.55; p < 0.02). In susceptible persons, anorexigens can cause an irreversible syndrome of PHT, hypoxemia, and systemic vascular complications after brief expos ures. These patients have a relative NO deficiency years after discont inuing the anorexigen, perhaps explaining their original susceptibilit y.