Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats

Abstract

1 Endothelin (ET) is a potent vasoconstrictor peptide which has been shown to have an important role in the regulation of systemic and renal haemodynamics. In order to elucidate the role of endogenous ET in the kidney, we examined the effects of ET receptor antagonists on systemic and renal vasculature in normotensive anaesthetized rats. 2 Intravenous injection of a selective ETA receptor antagonist, FR139317 (0.5 μmol kg-1, for 20 min) induced a very small fall in blood pressure. Similarly, a non-selective ET(A)/ET(B), receptor antagonist, TAK-044 (12.5/μmol kg-1, for 20 min) slightly decreased blood pressure. A selective ET(B) receptor antagonist, BQ-788 (0.5 μmol kg-1, for 20 min) had no effect on blood pressure. 3 FR139317 and TAK-044 did not affect renal blood flow or calculated renal vascular resistance. In contrast, BQ-788 significantly reduced renal blood flow by 18.2 ± 2.4% and increased renal vascular resistance. Furthermore, the renal vascular action of BQ-788 was not observed when combined with FR139317. 4 Pretreatment with a nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 37 μmol kg-1, i.v.) and a cyclo-oxygenase inhibitor ibuprofen (44 μmol kg-1, i.v.) completely abolished the BQ-788-mediated renal vasoconstriction. 5 These results indicate that activation of ET(B) receptors by endogenous ET acts as a physiological brake for the ET(A)-mediated renal vasoconstriction; this effect appears to be mediated by stimulation of NO and/or vasodilator prostaglandin(s) release.