NO and NO-independent mechanisms mediate ETBreceptor buffering of ET-1-induced renal vasoconstriction in the rat

Abstract

Vascular endothelin (ET) type B (ETB) receptors exert dilator and constrictor actions in a complex interaction with ETAreceptors. We aimed to clarify the presence and relative importance of nitric oxide (NO) and other mechanisms underlying the dilator effects of ETBreceptors in rat kidneys. Complete inhibition of NO production with Nω-nitro-l-arginine methyl ester (l-NAME, 25 mg/kg iv) enhanced the renal vasoconstriction elicited by ET-1 injected into the renal artery from −15 to −30%. Additional infusion of the NO donor nitroprusside (NP) into the renal artery did not reverse this effect (−29%) but effectively buffered ANG II-mediated vasoconstriction. Similarly, ET-1 responses were enhanced after a smaller intrarenal dose of l-NAME (−22 vs. −15%) and were unaffected by subsequent NP infusion (−21%). These results indicate that the responsiveness to ET-1 is buffered by ETBreceptor-stimulated phasic release of NO, rather than its static mean level. Infusion of the ETBreceptor antagonist BQ-788 into the renal artery further enhanced the ET-1 constrictor response to NP + l-NAME (−92 vs. −49%), revealing an NO-independent dilator component. In controls, vasoconstriction to ET-1 was unaffected by vehicle (−27 vs. −20%) and markedly enhanced by BQ-788 (−70%). The same pattern was observed when indomethacin (Indo) was used to inhibit cyclooxygenase (−20% for control, −22% with Indo, and −56% with ETBantagonist) or methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide (MS-PPOH) or miconazole + Indo was used to inhibit epoxygenase alone (−10% for control, −11% with MS-PPOH, and −35% with ETBantagonist) or in combination (−14% for control, −20% with Indo + miconazole, and −43% with ETBantagonist). We conclude that phasic release of NO, but not its static level, mediates part of the dilator effect of ETBreceptors and that an NO-independent mechanism, distinct from prostanoids and epoxyeicosatetraenoic acids, perhaps ETBreceptor clearance of ET-1, plays a major buffering role.