Dagassan P H, Breu V, Clozel M, Künzli A, Vogt P, Turina M, Kiowski W, Clozel J P
Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
J Cardiovasc Pharmacol. 1996 Jan;27(1):147-53. doi: 10.1097/00005344-199601000-00023.
Both endothelin-A (ETA) and endothelin-B (ETB) receptors are known to be present in human coronary arteries. However, their absolute and relative amounts, functional roles, and the influence of pathology are uncertain. The goal of the present study was to characterize endothelin receptors mediating constriction in human coronary arteries and to assess the influence of cardiomyopathy (CMP) and coronary artery disease (CAD) on ET receptors in human tissue. For comparison, porcine coronary arteries were evaluated in parallel. Competition binding experiments using [125I]ET-1 and different selective and nonselective ETA- and ETB-receptor agonists or antagonists revealed similar relative densities (relative Bmax) of ETA and ETB receptors in coronary arteries from human cardiomyopathic hearts (83% ETA and 17% ETB; n = 5) and porcine hearts (78% ETA and 22% ETB; n = 5). In marked contrast, the relative Bmax of ETB receptors were significantly higher in coronary arteries from human atherosclerotic hearts (51% ETA and 49% ETB; n = 3). Total receptor density (Bmax; fmol/mg protein) was highest in porcine (385 +/- 29) arteries, followed by human CAD (253 +/- 41) and CMP (174 +/- 20) coronary arteries. The relative and absolute Bmax values for ETA and ETB receptors in coronary arteries from a donor heart were similar to those obtained in CMP hearts. There were no significant differences in affinity constants (KD) values for ET-1, ET-3, Sarafotoxin S6c (SRTX S6c), BQ-123, and bosentan (Ro 47-0203) between tissues. In human coronary arteries from CMP hearts, ET-induced constriction seemed to be solely mediated via ETA receptors. In contrast, in porcine coronary arteries 20% of the maximal effect mediated by ET-1 could be attributed to ETB receptors, in agreement with the binding data. The functional role of ETB receptors in CAD tissue could not be evaluated because of the occurrence of spontaneous phasic contractions. We conclude that ETB receptors are up-regulated in human atherosclerotic coronary arteries. Further studies are needed to determine the pathophysiological importance of these receptors.
已知内皮素 -A（ETA）受体和内皮素 -B（ETB）受体均存在于人类冠状动脉中。然而，它们的绝对和相对含量、功能作用以及病理影响尚不确定。本研究的目的是表征介导人类冠状动脉收缩的内皮素受体，并评估心肌病（CMP）和冠状动脉疾病（CAD）对人体组织中ET受体的影响。为作比较，同时对猪冠状动脉进行了评估。使用[125I]ET -1以及不同的选择性和非选择性ETA和ETB受体激动剂或拮抗剂进行的竞争结合实验表明，人类心肌病心脏冠状动脉中ETA和ETB受体的相对密度（相对Bmax）相似（83%为ETA，17%为ETB；n = 5），猪心脏冠状动脉中也是如此（78%为ETA，22%为ETB；n = 5）。与之形成显著对比的是，人类动脉粥样硬化心脏冠状动脉中ETB受体的相对Bmax显著更高（51%为ETA，49%为ETB；n = 3）。总受体密度（Bmax；fmol/mg蛋白）在猪冠状动脉（385±29）中最高，其次是人类CAD冠状动脉（253± 41）和CMP冠状动脉（174±20）。供体心脏冠状动脉中ETA和ETB受体的相对和绝对Bmax值与CMP心脏中获得的值相似。各组织之间，ET -1、ET -3、Sarafotoxin S6c（SRTX S6c）、BQ -123和波生坦（Ro 47 - 0203）的亲和常数（KD）值没有显著差异。在CMP心脏的人类冠状动脉中，ET诱导的收缩似乎仅通过ETA受体介导。相比之下，在猪冠状动脉中，ET -1介导的最大效应的20%可归因于ETB受体，这与结合数据一致。由于出现自发性相位性收缩，无法评估CAD组织中ETB受体的功能作用。我们得出结论，人类动脉粥样硬化冠状动脉中ETB受体上调。需要进一步研究以确定这些受体的病理生理重要性。
