Endothelin B receptors on human endothelial and smooth-muscle cells show equivalent binding pharmacology.
We have described the pharmacologic profiles of endothelin B receptors in human endothelial cells and vascular and nonvascular smooth-muscle cells. First, by amplifying endothelin B receptor numbers through the use of phosphoramidon and intact cell-binding techniques, we demonstrated the presence of these receptors in human umbilical vein endothelial cells (100% endothelin B receptors), human aortic smooth-muscle cells (22% endothelin B, 78% endothelin A receptors), and human bronchial smooth-muscle cells (55% endothelin B, 45% endothelin A receptors) by using [125I]-endothelin-1 radioligand binding. The typical binding profiles of the endothelin B receptors were established through competition binding curve analysis with endothelin-1, endothelin-3, sarafotoxin 6c, and the endothelin A receptor-selective antagonist BQ-123. In the presence of BQ-123, a diverse group of antagonists, including PD 142893, BQ-788, SB 209670, and Ro 47-0203, were used to probe for binding differences indicative of multiple endothelin B-receptor subtypes. The results indicate a rank order of potency for the antagonists of BQ-788 > SB 209670 > PD 142893 > Ro 47-0203 for each cell line, and that between any of these human cell lines, measurements of [125I]-endothelin-1-binding antagonism for each of the four test compounds differed by less than twofold. Although this study cannot discount the possibility of more than one endothelin B-receptor subtype in humans, it does indicate that these tissues express receptors that show equivalent binding pharmacology.
Flynn
M A
MA
Department of Cardiovascular Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48106, USA.
Haleen
S J
SJ
Welch
K M
KM
Cheng
X M
XM
Reynolds
E E
EE
D001667:Binding, Competitive / Q000187:drug effects; D000077300:Bosentan; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011869:Radioligand Assay; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D007202:Indicators and Reagents; D009842:Oligopeptides; D010456:Peptides, Cyclic; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; C076213:PD 142893; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)