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

Abstract

Vascular endothelin (ET) type B (ET(B)) receptors exert dilator and constrictor actions in a complex interaction with ET(A) receptors. We aimed to clarify the presence and relative importance of nitric oxide (NO) and other mechanisms underlying the dilator effects of ET(B) receptors in rat kidneys. Complete inhibition of NO production with Nomega-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 ET(B) receptor-stimulated phasic release of NO, rather than its static mean level. Infusion of the ET(B) receptor 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 ET(B) antagonist) 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 ET(B) antagonist) or in combination (-14% for control, -20% with Indo + miconazole, and -43% with ET(B) antagonist). We conclude that phasic release of NO, but not its static level, mediates part of the dilator effect of ET(B) receptors and that an NO-independent mechanism, distinct from prostanoids and epoxyeicosatetraenoic acids, perhaps ET(B) receptor clearance of ET-1, plays a major buffering role.

Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O2− dismutation on renal autoregulation in the time and frequency domains

“…In addition to eliciting vasodilation, NO blunts vasoconstriction produced by G protein-coupled agonists, such as ANG II, endothelin-1, and the catecholamines norepinephrine or phenylephrine (9,38,40). Exaggerated vasoconstriction by one of these agonists might explain the enhanced myogenic response during NOS inhibition.…”

Short-term ANG II produces renal vasoconstriction independent of TP receptor activation and TxA2/isoprostane production

“…The surgical preparation is standard for acute RBF experiments (4,13,25). Briefly, an animal was anesthetized by injection of pentobarbital sodium (65 mg/kg body wt ip) and placed on a heating table that maintained body temperature at 37°C.…”

“…RBF and AP were recorded continuously, using conventional methodology (4,13,25). During the final 30 min of ANG II infusion in the two experimental groups, the TP receptor antagonist SQ29548 (180 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was coinfused into the renal artery (ira).…”

Endothelin-Induced Increased Nitric Oxide Mediates Augmented Distal Nephron Acidification as a Result of Dietary Protein

“…In addition to increasing renal production of endothelin, increased dietary protein increases urine excretion of nitric oxide (NO) metabolites (4). Furthermore, endothelin increases renal NO production (5), and NO increases acidification in the proximal (6) and distal (7) nephron. Consequently, we tested the hypothesis that increased renal endothelin production that is induced by increased dietary protein reduces distal nephron HCO 3 secretion through increased NO.…”