We have previously reported a significant contribution of ETA- and ETB-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 brochoconstrictive 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 (300-350g) and rapidly suspended and perfused (3 ml/min) with oxygenated Krebs solution at 37°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 ETA antagonist, BQ-123 (1 μM). The ET-1-induced vasoconstriction was restored 50 min after the cessation of BQ-123 infusion. In contrast, the selective ETB-receptor agonist, IRL-1620 (1-1000 pmol) was found to be inactive. Indomethacin (5 μM) and the ETB-receptor antagonist, BQ-788 (10 nM) did not affect the constrictor effect of ET-1. The infusion of ET-1 (0.5 and 1 μM, 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 μM) 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).
Address correspondence and reprint requests to Pedro D'Orléans-Juste, Institute of Pharmacology, Medical School, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada. E-mail: [email protected]
© 2000 Lippincott Williams & Wilkins, Inc.