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.
Fukuroda
T
T
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
Nishikibe
M
M
D000818:Animals; D065128:Endothelin Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C105142:BQ 928; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)