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 hypertension. The hemodynamic effects of ET-1 are due to activation of its receptors. The ETAreceptor mediates vasoconstriction and smooth muscle cell proliferation, whereas the ETBreceptor mediates vasodilation. In a lamb model of chronic intrauterine pulmonary hypertension, ETBreceptor activity and gene expression are decreased. To determine whether prolonged ETBreceptor blockade causes pulmonary hypertension, we studied the hemodynamic effects of selective ETBreceptor blockade with BQ-788. Animals were treated with an infusion of either BQ-788 or vehicle for 7 days. Prolonged BQ-788 treatment increased pulmonary arterial pressure and pulmonary vascular resistance ( P < 0.05). The pulmonary vasodilator response to sarafotoxin 6c, a selective ETBreceptor agonist, was attenuated after 7 days of BQ-788 treatment, demonstrating pharmacological blockade of the ETBreceptor. Animals treated with BQ-788 had greater right ventricular hypertrophy and muscularization of small pulmonary arteries ( P < 0.05). Lung ET-1 levels were threefold higher in the animals treated with BQ-788 ( P < 0.05). We conclude that prolonged selective ETBreceptor blockade causes severe pulmonary hypertension and pulmonary vascular remodeling in the late-gestation ovine fetus.