Cardiovascular and renal actions of the endothelin(B) receptor in pigs.
Previously we showed that blocking the endothelin (ET)A receptor subtype with BQ-153 inhibited the vasoconstrictor effects of intravenously administered ET-1. In the presence of the ET(A) antagonist, ET-1 produced marked reductions in myocardial contractility and renal blood flow. We postulated that either the ET(B) receptor, or some other, as yet unidentified, ET-receptor subtype mediated the observed hemodynamic changes. In anesthetized pigs, this hypothesis was tested by using a recently developed selective, high-affinity antagonist to the ET(B) receptor, BQ-788, and sarafotoxin S6c, a selective ET(B) agonist, to determine the contribution of this receptor subtype to cardiovascular function. Endothelin-1 (0.4 nmol/kg, i.v.) produced the characteristic biphasic hemodynamic responses, consisting of an initial transient reduction in mean arterial pressure (MAP; 83 +/- 3 to 72 +/- 4 mm Hg; n = 9) followed by a prolonged increase (112 +/- 4 mm Hg; p < 0.01). As well, cardiac output (-58%; p < 0.05), myocardial contractility (-19%; p < 0.01), and renal blood flow (63%; p < 0.05) decreased. Sarafotoxin S6c produced marked but transient reductions in MAP (p < 0.001), cardiac output (p < 0.01), myocardial contractility (p < 0.001), and renal blood flow (p < 0.05). BQ-788 (1.0 mg/kg, i.v.), administered 3 min before sarafotoxin S6c, inhibited its effects. BQ-788 also inhibited the initial transient reduction in MAP seen after the injection of ET-1, but the subsequent sustained pressor responses were enhanced as reflected in the greater increases in left ventricular pressure (p < 0.02), myocardial contractility (p < 0.05), MAP (p < 0.01), and a larger reduction in cardiac output (p < 0.05). The heart rate was not changed after the initial ET injection, but it increased 54% when the peptide was administered in the presence of BQ-788. The reduction in renal blood flow was still evident, and its magnitude (64%) remained the same (p < 0.01) after treatment with BQ-788. Only the combined administration of both the ET(A) (BQ-123) and ET(B) (BQ-788) receptor antagonists blocked the effects of ET-1 on renal blood flow (p < 0.05). These data confirm that BQ-788 is a selective and effective antagonist of the ET(B) receptor and show that activation of this receptor subtype is involved in the transient vasodilation provoked by ET-1. Additionally, the ET(B) receptor appears to oppose the vasoconstrictor effects of the ET(A) receptor, which clearly mediates vasoconstriction. Combined treatment with BQ-123 and BQ-788 attenuated the reductions in renal blood flow produced by ET-1. Furthermore, some actions of ET-1 were not blocked by these antagonists and cannot be attributed to either the ET(A) or ET(B) receptors. We hypothesize the existence of an additional ET receptor or a subtype of the ET(B) receptor that is insensitive to BQ-788.
Cirino
M
M
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
Martin
E
E
Yano
M
M
Rodger
I W
IW
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects*; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)