Up-regulation of endothelin-B receptors in atherosclerotic human coronary arteries

Both endothelin-A (ET(A)) and endothelin-B (ET(B)) 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 [I-125]ET-1 and different selective and nonselective ET(A)- and ET(B)-receptor agonists or antagonists revealed similar relative densities (relative B-max) of ET(A) and ET(B) receptors in coronary arteries from human cardiomyopathic hearts (83% ET(A) and 17% ET(B); n = 5) and porcine hearts (78% ET(A) and 22% ET(B); n = 5). In marked contrast, the relative B-max of ET(B) receptors were significantly higher in coronary arteries from human atherosclerotic hearts (51% ET(A) and 49% ET(B); n = 3). Total receptor density (B-max; 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 B-max values for ET(A) and ET(B) receptors in coronary arteries from a donor heart were similar to those obtained in CMP hearts. There were no significant differences in affinity constants (K-D) 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 ET(A) receptors. In contrast, in porcine coronary arteries 20% of the maximal effect mediated by ET-1 could be attributed to ET(B) receptors, in agreement with the binding data. The functional role of ET(B) receptors in CAD tissue could not be evaluated because of the occurrence of spontaneous phasic contractions. We conclude that ET(B) receptors are up-regulated in human atherosclerotic coronary arteries. Further studies are needed to determine the pathophysiological importance of these receptors.