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Am J Physiol Lung Cell Mol Physiol 279: L758-L765, 2000;
1040-0605/00 $5.00
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Vol. 279, Issue 4, L758-L765, October 2000

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

D. Dunbar Ivy1, Thomas A. Parker2, and Steven H. Abman3

Sections of 1 Cardiology, 2 Neonatology, and 3 Pulmonary Medicine, Pediatric Heart Lung Center, University of Colorado School of Medicine, and The Children's Hospital, Denver, Colorado 80218

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 ETA receptor mediates vasoconstriction and smooth muscle cell proliferation, whereas the ETB receptor mediates vasodilation. In a lamb model of chronic intrauterine pulmonary hypertension, ETB receptor activity and gene expression are decreased. To determine whether prolonged ETB receptor blockade causes pulmonary hypertension, we studied the hemodynamic effects of selective ETB receptor 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 ETB receptor agonist, was attenuated after 7 days of BQ-788 treatment, demonstrating pharmacological blockade of the ETB receptor. 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 ETB receptor blockade causes severe pulmonary hypertension and pulmonary vascular remodeling in the late-gestation ovine fetus.

nitric oxide; persistent pulmonary hypertension of the newborn; congenital heart disease; pulmonary circulation; BQ-788


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