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 ET(B)-receptor agonist, sarafotoxin S6c (0.01-1 muM), failed to elicit vasoconstriction in this tissue. Thus, endothelin isopeptide-induced vasoconstriction of the canine isolated pulmonary artery is mediated exclusively by the ET(A)-receptor subtype. 3 The concentration-dependent increases in isometric tension induced by endothelin-1 (0.1-300 nM) were antagonized by the ET(A)-selective antagonist, BQ-123 (10 muM); 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 ET(B)-receptor-mediated vasoconstriction since sarafotoxin S6c (0.01-1 muM) 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 muM), 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.