Effects of dexfenfluramine on hypoxic pulmonary vasoconstriction and embolic pulmonary hypertension in dogs.
There has been suggestion of a possible relationship between the intake of the appetite suppressant dexfenfluramine and the development of primary pulmonary hypertension. We investigated the pulmonary vascular effects of acute intravenous dexfenfluramine in pentobarbital-anesthetized dogs ventilated in hyperoxia (fraction of inspired oxygen, FIO2, 0.4) and either challenged with a FIO2 of 0.1 to induce hypoxic pulmonary hypertension (n = 20) or given autologous blood clots to induce embolic pulmonary hypertension (n = 6). Pulmonary vascular tone was evaluated by multipoint (mean pulmonary artery pressure [Ppa] - pulmonary artery occluded pressure [Ppao])/cardiac output (Q) plots. Hypoxia increased Ppa - Ppao over the entire range of Q studied, from 1.5 to 4.0 L/min/m2, in 12 dogs (responders) and had no significant effect on (Ppa - Ppao)/Q plots in 8 other dogs (nonresponders). Dexfenfluramine did not affect (Ppa - Ppao)/Q plots in 6 responders but shifted (Ppa - Ppao)/Q plots to higher pressures in hypoxia in 6 nonresponders (p < 0.001). Dexfenfluramine had no effect on (Ppa - Ppao)/Q plots in the 6 dogs with embolic pulmonary hypertension. Because dexfenfluramine has serotoninergic properties, we compared the effects of ketanserin, a serotonin (5-hydroxytryptamine, 5-HT) S2 receptor antagonist, on naturally present versus dexfenfluramine-restored hypoxic pulmonary vasoconstriction. Ketanserin did not affect hyperoxic or hypoxic pulmonary vascular tone, neither in 6 responders nor in 2 nonresponders with dexfenfluramine-restored hypoxic vasoconstriction. We conclude that dexfenfluramine restores hypoxic pulmonary vasoconstriction in dogs with weak or absent hypoxic pressor response and that this effect is unlikely to be mediated by activation of 5-HT S2 receptors.
Naeije
R
R
Laboratory of Cardiovascular and Respiratory Physiology, Erasme University Hospital, Brussels, Belgium.
Wauthy
P
P
Maggiorini
M
M
Leeman
M
M
Delcroix
M
M
D000818:Animals; D004285:Dogs; D005277:Fenfluramine / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D007650:Ketanserin / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D011655:Pulmonary Embolism / Q000503:physiopathology*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
D011985:Receptors, Serotonin; D005277:Fenfluramine; D007650:Ketanserin