Effect of chronic hypoxia on endothelin receptors of isolated pulmonary arteries of rats

Abstract

Circulating levels of endothelin (ET) arc raised in babies with pulmonary hypertension of the newborn. Chronic exposure to hypobaric hypoxia causes pulmonary hypertension in rats, which similarly results in abnormalities in the pulmonary arterial structure. Therefore, we studied the effect of chronic hypoxia on the ET receptors of isolated pulmonary arteries from the rat. Treatment of arteries from normoxic rats with ET-1 produced net vasoconstriction, which was significantly inhibited by the ETA receptor antagonist, BQ610, suggesting that constriction was mainly mediated by ETA receptors in this preparation. Stimulation of ETB receptors resulted in a transient vasodilation, followed by a small net vasoconstriction. It has been reported that the transient vasodilation is mediated by endothelial ETB receptors. whereas the vasoconstriction is mediated by ETB receptors on the vascular smooth muscle. Treatment with the ETB receptor antagonist, BQ 788, abolished the initial vasodilation, confirming the presence of ETB dilator receptors in the normoxic pulmonary artery preparation. The constrictor response to a high dose of ET-1 (5x10 -8M) was significantly lower in hypoxic rats compared to normoxic rats. In the presence of the ETB receptor antagonist, BQ788, the constrictor responses to low doses of ET-1 (10 -9-5x10 -9M) were also significantly less in hypoxic than in normoxic vessels, suggesting that ETA-receptor-mediated vasoconstriction was diminished in chronic hypoxia. In the presence of the ETA receptor anatognist, BQ610, there was significantly more constriction from hypoxic than from normoxic vessels in response to 10—8M ET-1, but no difference between the response to 10 -7M ET-1, suggesting that ETB-mediated dilation was also diminished in chronic hypoxia. Thus, at low ET concentrations, there was no net change in the response to ET in hypoxic vessels, but at high ET concentrations, th ETB dilator receptors were saturated and decreased ETA-mediated constriction became apparent.