Endothelin-1 induces an endothelin-A-receptor-dependent and L-NAME-sensitive vasoconstriction in the isolated perfused guinea-pig kidney.
We have previously reported a significant contribution of ET(A)- and ET(B)-receptors in the eicosanoid-releasing properties of endothelin-1 (ET-1) in the guinea-pig perfused lung. More recently, it was found that intravenously administered ET-1 in the guinea-pig triggers the release of hypotensive and bronchoconstrictive eicosanoids which is strongly modulated by endogenous nitric oxide. In this study we investigate the contribution of both ET receptors as well as of the eicosanoids and nitric oxide to the vasoconstrictor properties of ET-1 in the guinea-pig kidney. The kidney was isolated from stunned and spinal cord-sectioned guinea-pig (300-350 g) and rapidly suspended and perfused (3 ml/min) with oxygenated Krebs solution at 37 degrees C. ET-1 (1-1000 pmol) induced dose-dependent increases in perfusion pressure in the perfused guinea-pig kidney. Furthermore, the pressor effect of a dose of ET-1 (40 pmol) was markedly reduced after a 15-min infusion of the ET(A) antagonist, BQ-123 (1 microM). The ET-1-induced vasoconstriction was restored 50 min after the cessation of BQ-123 infusion. In contrast, the selective ET(B)-receptor agonist, IRL-1620 (1-1000 pmol) was found to be inactive. Indomethacin (5 microM) and the ET(B)-receptor antagonist, BQ-788 (10 nM) did not affect the constrictor effect of ET-1. The infusion of ET-1 (0.5 and 1 microM, 5 min) in the guinea-pig kidney did not induce the release of prostacyclin or thromboxane. Finally, a 60 min infusion with the nitric oxide synthase inhibitor, L-NAME (200 microM) markedly potentiated the constrictor effects of ET-1. Our results suggest that unlike the pulmonary vasculature, the guinea-pig kidney responds to ET-1 by a direct constriction, which is modulated by nitric oxide but not eicosanoids (supported by the MRCC).
Duval
M
M
Institute of Pharmacology, Medical School, Université de Sherbrooke, Québec, Canada.
D'Orléans-Juste
P
P
D000818:Animals; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010477:Perfusion; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*
D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C074308:sovateltide; D009569:Nitric Oxide; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D019331:NG-Nitroarginine Methyl Ester