Effect of BQ-123 and Ro 47-0203 (bosentan) on endothelin-induced vasoconstriction in the rat skin.
The effectiveness of intradermal (i.d.) BQ-123 (cyclo[D-Asp-Pro-D-Val-Leu-D-Trp]) and i.d. Ro 47-0203 (bosentan, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4 - yl]-benzene-sulfonamide) has been evaluated on local microvascular responses to endothelin-1 and endothelin-3, measured by a multiple site 133Xe clearance technique in rat skin in vivo. Intradermal injection of endothelin-1 (0.3 pmol/site) and endothelin-3 (10 pmol/site) induced a similar (approximately 50-60%) decrease in basal blood flow in rat skin. BQ-123 (3-1000 pmol/site), a selective endothelin ETA receptor antagonist, caused a significant dose-dependent decrease in the vasoconstriction induced by endothelin-1 (P < 0.05) but was less effective on vasoconstriction induced by endothelin-3. Bosentan (3-1000 pmol/site), a new non-peptide mixed antagonist of endothelin ETA and endothelin ETB receptors, significantly reduced the vasoconstriction induced by endothelin-1 but was less effective than BQ-123. BQ-123 and bosentan were similarly effective as antagonists of endothelin-3. BQ-123 and bosentan had no effect on basal blood flow and no inhibitory activity on vasoconstriction induced by vasopressin (0.03 pmol/site) or phenylephrine (300 pmol/site). These findings indicate that BQ-123 and bosentan are effective and selective inhibitors of the vasoconstriction induced by endothelins in the rat skin microvasculature.
Lawrence
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Biomedical Sciences Division, King's College, London, UK.
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D000818:Animals; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007271:Injections, Intradermal; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply* / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014667:Vasopressins / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D013449:Sulfonamides; D014667:Vasopressins; D010656:Phenylephrine; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)