Enhancement of Pulmonary Artery Contraction Induced by Endothelin-B Receptor Antagonism

We previously reported that endothelin (ET)A and ETB receptors are involved in ET-1-induced contraction in isolated rabbit pulmonary artery and human bronchus. However, the activity of an ETA/ETB dual antagonist was lower than expected in these tissues. In such ETA/ETB receptor composite-type tissues, low doses of the ETB antagonist BQ-788 shifted the concentration-contraction curve for ET-1 slightly to the left, implying potentiation of contraction. Therefore, we investigated the potentiation of contraction by ETB antagonism in isolated rabbit pulmonary artery. In endothelium-denuded artery segments, ET-1 (10(-10) M) elicited sustained, almost half-maximal contraction. BQ-123 up to 10(-6) M did not affect contractile tone in ET-1-precontracted artery segments. In contrast, the ETB-selective antagonist BQ-788 (10(-8) M to 10(-7) M) enhanced contraction in ET-1-precontracted artery. In addition, in endothelium-intact artery samples, BQ-788 enhanced contraction to the same extent as in endothelium-denuded artery. In the presence of 10(-6) M BQ-123, BQ-788 failed to enhance contraction, and concentrations > 10(-7) M elicited only relaxation. The present results suggest that blockade of ETB receptors increases contractile tone through an endothelium-independent mechanism, possibly by inhibition of ETB-mediated regional clearance of ET-1 and/or of an ETB-mediated inhibitory mechanism, in rabbit pulmonary artery. This action may explain the decreased potency of ETA/ETB dual antagonists in ETA/ETB composite-type tissue responses.