title: Why big endothelin-1 lacks a vasodilator response.
abstract: The biphasic arterial blood pressure response to endothelin-1 (ET-1) results from a transient decrease, followed by a longer-lasting increase, in systemic vascular resistance. In contrast to ET-1, big endothelin-1 (bET-1) produces monophasic increases in systemic vascular resistance and arterial blood pressure. This is somewhat surprising, because bET-1 activity is reportedly due to ET-1, bET-1 being converted to ET-1 by a putative converting enzyme. In this study we tested two hypotheses that could explain the singular effect of bET-1 on the arterial vasculature: that bET-1 vasoconstriction, mediated by ETA receptors at the level of the smooth muscle, masks the release of endothelial derived vasodilators, and/or that the endothelium develops tachyphylaxis owing to prolonged activation of endothelial ETB receptors. In anesthetized rats, blockade of the vasoconstrictor activity of bET-1 with BQ-123, an ETA-receptor antagonist, did not reveal a masked bET-1 vasodilator component in the rat hindquarter. Furthermore, in the presence of bET-1 (after 3.0 nmol/kg bET-1 i.v.), low doses of ET-1 (0.03-0.3 nmol/kg) produced dose-dependent hindquarter vasodilation, indicating activation of endothelial ETB and therefore no tachyphylaxis. Collectively, these experiments suggest that i.v. administration of bET-1 results in little or no activation of endothelial ETB receptors and therefore lacks a vasodilator response.
authors.affiliation: Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48105.
authors.forename: S J
authors.initials: SJ
authors.lastname: Haleen
authors.forename: L S
authors.initials: LS
authors.lastname: Davis
authors.forename: D M
authors.initials: DM
authors.lastname: LaDouceur
authors.forename: J A
authors.initials: JA
authors.lastname: Keiser
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply; D066298:In Vitro Techniques; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013618:Tachyphylaxis / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010456:Peptides, Cyclic; D011498:Protein Precursors; C072247:cyclo(Trp-Asp-Pro-Val-Leu)