ENDOTHELIN-RECEPTOR ANTAGONIST BOSENTAN PREVENTS AND REVERSES HYPOXICPULMONARY-HYPERTENSION IN RATS

The current study examined the effects of bosentan, an orally active a ntagonist of endothelin-A and -B receptors, on the development and mai ntenance of hypoxia (10% O-2)-induced pulmonary hypertension and vascu lar remodeling in the rat. Pretreatment with bosentan (100 mg . kg(-1) . day(-1), 1 gavage/day for 2 days) completely blocked the pulmonary vasoconstrictor response to acute hypoxia. Chronic bosentan treatment (100 mg . kg(-1) . day(-1) po in the food) instituted 48 h before hypo xic exposure prevented the subsequent development of pulmonary hyperte nsion, attenuated the associated right heart hypertrophy, and prevente d the remodeling of small (50-100 mu m) pulmonary arteries without alt ering systemic arterial pressure. Institution of bosentan treatment (f or 4 wk) after 2 wk of hypoxia produced a significant reversal of esta blished hypoxia-induced pulmonary hypertension (from 36 +/- 1 to 25 +/ - 1 mmHg), right heart hypertrophy, and pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypoth esis that endogenous endothelin-1 plays a major role in hypoxic pulmon ary vasoconstriction and/or hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that endothelin-receptor bl ockade may be useful in the treatment of hypoxic pulmonary hypertensio n in humans.