Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats.

Mechanisms by which endothelin (ET)-1 mediates chronic pulmonary hypertension remain incompletely understood. Although activation of the ET type A (ET(A)) receptor causes vasoconstriction, stimulation of ET type B (ET(B)) receptors can elicit vasodilation or vasoconstriction. We hypothesized that the ET(B) receptor attenuates the development of hypoxic pulmonary hypertension and studied a genetic rat model of ET(B) receptor deficiency (transgenic sl/sl). After 3 wk of severe hypoxia, the transgenic sl/sl pulmonary vasculature lacked expression of mRNA for the ET(B) receptor and developed exaggerated pulmonary hypertension that was characterized by elevated pulmonary arterial pressure, diminished cardiac output, and increased total pulmonary resistance. Plasma ET-1 was fivefold higher in transgenic sl/sl rats than in transgenic controls. Although mRNA for prepro-ET-1 was not different, mRNA for ET-converting enzyme-1 was higher in transgenic sl/sl than in transgenic control lungs. Hypertensive lungs of sl/sl rats also produced less nitric oxide metabolites and 6-ketoprostaglandin F(1alpha), a metabolite of prostacyclin, than transgenic controls. These findings suggest that the ET(B) receptor plays a protective role in the pulmonary hypertensive response to chronic hypoxia.