EFFECTS OF DEXFENFLURAMINE ON HYPOXIC PULMONARY VASOCONSTRICTION AND EMBOLIC PULMONARY-HYPERTENSION IN DOGS

There has been suggestion of a possible relationship between the intak e of the appetite suppressant dexfenfluramine and the development of p rimary pulmonary hypertension. We investigated the pulmonary vascular effects of acute intravenous dexfenfluramine in pentobarbital-anesthet ized dogs ventilated in hyperoxia (fraction of inspired oxygen, FlO(2) , 0.4) and either challenged with a FlO(2) of 0.1 to induce hypoxic pu lmonary hypertension (n = 20) or given autologous blood clots to induc e embolic pulmonary hypertension (n = 6). Pulmonary vascular tone was evaluated by multipoint (mean pulmonary artery pressure [Ppa] - pulmon ary 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/m(2), in 12 dogs (responders) and had no significant effect on (Ppa - Ppao)/Q plots in 6 other dogs (nonresponders). Dexfenflurami ne did not affect (Ppa - Ppao)/Q plots in 6 responders but shifted (Pp a - Ppao)/Q plots to higher pressures in hypoxia in 6 nonresponders (p < 0.001). Dexfenfluramine had no effect on (Ppa - Ppao)/Q plots in th e 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 nat urally present versus dexfenfluramine-restored hypoxic pulmonary vasoc onstriction. Ketanserin did not affect hyperoxic or hypoxic pulmonary vascular tone, neither in 6 responders nor in 2 nonresponders with dex fenfluramine-restored hypoxic vasoconstriction. We conclude that dexfe nfluramine restores hypoxic pulmonary vasoconstriction in dogs with we ak or absent hypoxic presser response and that this effect is unlikely to be mediated by activation of 5-HT S2 receptors.