Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension

Am J Respir Crit Care Med. 1998 Oct;158(4):1061-7. doi: 10.1164/ajrccm.158.4.9802113.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Angina Pectoris / chemically induced
  • Appetite Depressants / adverse effects*
  • Case-Control Studies
  • Dexfenfluramine / adverse effects*
  • Disease Susceptibility
  • Female
  • Fenfluramine / adverse effects*
  • Free Radical Scavengers / blood
  • Free Radical Scavengers / metabolism*
  • Humans
  • Hypertension / chemically induced
  • Hypertension, Pulmonary / chemically induced*
  • Hypoxia / chemically induced
  • Ischemic Attack, Transient / chemically induced
  • Lung / blood supply
  • Lung / metabolism
  • Male
  • Middle Aged
  • Nitric Oxide / blood
  • Nitric Oxide / deficiency
  • Nitric Oxide / metabolism*
  • Oxidation-Reduction
  • Physical Exertion / physiology
  • Prospective Studies
  • Rest / physiology
  • Vascular Resistance / drug effects


  • Appetite Depressants
  • Free Radical Scavengers
  • Fenfluramine
  • Nitric Oxide
  • Dexfenfluramine