Prolonged endothelin B receptor blockade causes pulmonary hypertension in the ovine fetus

Endothelin (ET)-1 contributes to regulation of pulmonary vascular tone and structure in the normal ovine fetus and in models of perinatal pulmonary hy pertension. The hemodynamic effects of ET-1 are due to activation of its re ceptors. The ETA receptor mediates vasoconstriction and smooth muscle cell proliferation, whereas the ETB receptor mediates vasodilation. In a lamb mo del of chronic intrauterine pulmonary hypertension, ETB receptor activity a nd gene expression are decreased. To determine whether prolonged ETB recept or blockade causes pulmonary hypertension, we studied the hemodynamic effec ts of selective ETB receptor blockade with BQ-788. Animals were treated wit h an infusion of either BQ-788 or vehicle for 7 days. Prolonged BQ-788 trea tment increased pulmonary arterial pressure and pulmonary vascular resistan ce (P < 0.05). The pulmonary vasodilator response to sarafotoxin 6c, a sele ctive ETB receptor agonist, was attenuated after 7 days of BQ-788 treatment , demonstrating pharmacological blockade of the ETB receptor. Animals treat ed with BQ-788 had greater right ventricular hypertrophy and muscularizatio n of small pulmonary arteries (P < 0.05). Lung ET-1 levels were threefold h igher in the animals treated with BQ-788 (P < 0.05). We conclude that prolo nged selective ETB receptor blockade causes severe pulmonary hypertension a nd pulmonary vascular remodeling in the late-gestation ovine fetus.