THE ENDOTHELIN ANTAGONIST BOSENTAN - HEMODYNAMIC-EFFECTS DURING NORMOXIA AND HYPOXIA PULMONARY-HYPERTENSION IN PIGS

In this study, we investigated the hemodynamic effects and receptor-bl ocking properties of the nonselective endothelin antagonist bosentan i n pigs during normoxia and acute hypoxia. Hypoxic pulmonary hypertensi on was induced by decreasing the fraction of inhaled oxygen to 0.1, Tn a control group of pigs, hemodynamic parameters proved to be stable t hrough 2 hours of hypoxia. Infusions of endothelin-1, endothelin-3, an d sarafotoxin 6c into the pulmonary artery resulted in pulmonary and s ystemic vasoconstriction during normoxia. whereas endothelin administr ation during hypoxic pulmonary hypertension resulted in pulmonary vaso dilation. After administration of bosentan, the vasopressor effect of endothelin-1 during normoxia was significantly attenuated and the pulm onary vasodilatory effect of endothelin-1 during hypoxia was reduced, Furthermore, the development of hypoxic pulmonary hypertension was sig nificantly reduced by bosentan, In contrast, bosentan did not influenc e the pulmonary vasopressor response to the thromboxane mimic U-46619. We therefore conclude that vasopressor endothelin receptors seem to b e activated by endogenous endothelin released during hypoxia, leading to an increase in the pulmonary vascular tone.