Effects of chronic dexfenfluramine treatment on pulmonary hemodynamics in dogs.
An epidemic of primary pulmonary hypertension occurred in Europe in the 1960s, after the introduction of the appetite suppressant aminorex. Recently, a cluster of cases of pulmonary hypertension was observed in France in relation to the intake of the appetite suppressant dexfenfluramine. We previously reported that intravenous dexfenfluramine enhances hypoxic pulmonary vasoconstriction in dogs. We therefore investigated the pulmonary hemodynamic effects of chronic oral intake of this drug. Twenty-four dogs with a strong (n = 12) and a weak hypoxic pulmonary vasoconstriction (n = 12) respectively were randomly allocated in a double blind manner to a twice daily oral intake of either a placebo or dexfenfluramine 1.5 mg/kg for 20 d. A strong hypoxic vasoconstriction was defined as a hypoxia-induced increase in pulmonary artery pressure by more than 3 mm Hg at a standardized cardiac output of 3 L/min/m2. Pulmonary hemodynamics were studied in hyperoxia (fraction of inspired O2 [F(I)O2] 0.4) and in hypoxia (F(I)O2 0.1) before and after treatment. Venous return was manipulated at post-treatment evaluation for isoflow comparisons of pulmonary vascular pressures. Dexfenfluramine had no effect on systemic hemodynamics or blood gases, but increased pulmonary vascular resistance from 155 +/- 17 to 192 +/- 14 dyne x s x cm(-5) in hyperoxia (mean +/- SE, p < 0.05) and from 237 +/- 27 to 293 +/- 47 dyne x s x cm(-5) in hypoxia (p < 0.01). Dexfenfluramine, and not placebo, increased the isoflow pulmonary vascular pressure gradient in hyperoxia and in hypoxia. This effect was unrelated to the magnitude of pretreatment hypoxic vasoconstriction. We conclude that the chronic intake of dexfenfluramine in dogs is associated with a moderate increase in pulmonary vascular resistance which is unrelated to pulmonary vasoreactivity to hypoxia.
Naeije
R
R
Laboratory of Cardiovascular and Respiratory Physiology, Erasme University Hospital, Brussels, Belgium.
Maggiorini
M
M
Delcroix
M
M
Leeman
M
M
Mélot
C
C
D000284:Administration, Oral; D000818:Animals; D001067:Appetite Depressants / Q000009:adverse effects* / Q000493:pharmacokinetics; D004285:Dogs; D005277:Fenfluramine / Q000009:adverse effects* / Q000493:pharmacokinetics; D006439:Hemodynamics / Q000187:drug effects*; D000860:Hypoxia / Q000188:drug therapy; D011669:Pulmonary Wedge Pressure / Q000187:drug effects
D001067:Appetite Depressants; D005277:Fenfluramine