Up-Regulation of Endothelin-B Receptors in Atherosclerotic Human Coronary Arteries

Abstract

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.

Acute Endothelin-Receptor Inhibition Does Not Attenuate Acetylcholine-Induced Coronary Vasoconstriction in Experimental Hypercholesterolemia

“…In diet-induced hypercholesterolemia and atherosclerosis, there is diffuse upregulation of the ETB receptor. 28,29 Furthermore, we 30 showed that in a canine experimental model of heart failure, which is associated with endothelial dysfunction, there is enhanced coronary vasoconstriction to ETB-receptor activation, albeit primarily at the level of the coronary microcirculation. It is thus possible that the contribution of endogenous ET to acetylcholine-induced coronary epicardial vasoconstriction in hypercholesterolemia is primarily mediated by ETB receptors, rather than by ETA receptors.…”

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ETB receptor

“…Furthermore, the importance of ETB receptors in pathological situations may be reflected by enhanced receptor densities as recently described for the aorta of spontaneously hypertensive rats [9], the basilar artery of rabbits after subarachnoidal hemorrhage [11] and for the rabbit carotid artery after balloon denudation [29]. Most recently, an upregulation of ETB receptors has also been demonstrated in human coronary arteries from atherosclerotic patients [10]. In order to further characterize the nature of these ETB receptors and to clarify the role of ETB receptors in pathology, ETB receptor selective antagonists are an essential tool.…”

“…Unfortunately, so far no data with corresponding human constricting ETB receptors are available. Efforts to measure sarafotoxin $6c mediated constriction in human atherosclerotic coronary arteries failed due to the occurrence of spontaneous phasic constrictions [10]. However, because similar binding potency and selectivity ratio was found between human and rat ETA and ETB receptors, Ro 46-8443 seems to display few if any species differences, suggesting a highly conserved binding site on the ET receptors.…”

“…The profound vasoconstriction is mediated both by [-I'A and ETB receptors located on smooth muscle cells [4-6. In addition, ETB receptors located on endothelial cells are a,~le to mediate vasodilatation through release of endothelium d, erived relaxing factor or prostacyclin [7]. Interestingly, certdn pathological situations have been associated with inc "eased density of ETB receptors [8][9][10][11], but the lack of ETB r'ceptor selective antagonists has hampered further elucidat on of the role of ETt~ receptors in pathology.…”

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

“…Patients with hypertension have increased endothelin receptor activity and an increased vascular tone (Li et al, 2007). The atherosclerotic arteries exhibit a similar receptor upregulation (Dagassan et al, 1996;Pernow et al, 2000), suggesting that this receptor upregulation takes place during pathological conditions. In human atherosclerotic lesions, there is also an increase in 18 ET-1 and ET B receptors and this increase is seen in the medial VSMC, just beneath the foam cells (Iwasa et al, 1999).…”