Endothelin-1 does not mediate hypoxic vasoconstriction in canine isolated blood vessels: effect of BQ-123.
1. The role of endothelin-1 in mediating the phenomenon of hypoxic vasoconstriction was examined in canine, isolated pulmonary, circumflex coronary and femoral arterial rings. 2. In tissues with an intact endothelium, the exogenous application of endothelin-1 (0.1-300 nM) caused concentration-dependent increases in canine, isolated pulmonary artery tone. Endothelin-3 (1-300 nM) was approximately 30 fold less potent than endothelin-1 as a vasoconstrictor in this tissue. In contrast, the selective ETB-receptor agonist, sarafotoxin S6c (0.01-1 microM), failed to elicit vasoconstriction in this tissue. Thus, endothelin isopeptide-induced vasoconstriction of the canine isolated pulmonary artery is mediated exclusively by the ETA-receptor subtype. 3. The concentration-dependent increases in isometric tension induced by endothelin-1 (0.1-300 nM) were antagonized by the ETA-selective antagonist, BQ-123 (10 microM); this concentration of antagonist caused a shift to the right in the concentration-response curve for endothelin-1 of approximately two orders of magnitude. This concentration of BQ-123 did not unmask any ETB-receptor-mediated vasoconstriction since sarafotoxin S6c (0.01-1 microM) still failed to elicit contraction in the presence of this concentration of BQ-123. 4. The hypoxia-induced vasoconstriction of canine, isolated pulmonary, circumflex coronary and femoral arterial rings was unaffected by pretreatment with the endothelin receptor antagonist, BQ-123 (10 microM), a concentration shown previously to antagonize the contractile actions of exogenously applied endothelin-1 in the isolated pulmonary artery. 5. These results are the first to provide direct evidence showing that the endothelium-dependent vasoconstriction observed during acute periods of hypoxia in vitro is not mediated by an endothelin-related isopeptide.
Douglas
S A
SA
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Vickery-Clark
L M
LM
Ohlstein
E H
EH
D000595:Amino Acid Sequence; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D016232:Endothelins / Q000502:physiology*; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D016232:Endothelins; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)