Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction

Endothelin (ET)-1 contributes to the regulation of pulmonary vascular tone by stimulation of the ET_A and ET_B receptors. Although activation of the ET_A receptor causes vasoconstriction, stimulation of the ET_B receptors can elicit either vasodilation or vasoconstriction. To examine the physiological role of the ET_B receptor in the pulmonary circulation, we studied a genetic rat model of ET_B receptor deficiency [transgenic(sl/sl)]. We hypothesized that deficiency of the ET_B receptor would predispose the transgenic(sl/sl) rat lung circulation to enhanced pulmonary vasoconstriction. We found that the lungs of transgenic(sl/sl) rats are ET_B deficient because they lack ET_B mRNA in the pulmonary vasculature, have minimal ET_B receptors as determined with an ET-1 radioligand binding assay, and lack ET-1-mediated pulmonary vasodilation. The transgenic(sl/sl) rats have higher basal pulmonary arterial pressure and vasopressor responses to brief hypoxia or ET-1 infusion. Plasma ET-1 levels are elevated and endothelial nitric oxide synthase protein content and nitric oxide production are diminished in the transgenic(sl/sl) rat lung. These findings suggest that the ET_B receptor plays a major physiological role in modulating resting pulmonary vascular tone and reactivity to acute hypoxia. We speculate that impaired ET_B receptor activity can contribute to the pathogenesis of pulmonary hypertension.