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This Article Full Text Full Text (PDF) All Versions of this Article: 288/5/R1168    most recent 00550.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Just, A. Articles by Arendshorst, W. J. Search for Related Content PubMed PubMed Citation Articles by Just, A. Articles by Arendshorst, W. J.

NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

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

¹Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and ²Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 12 August 2004 ; accepted in final form 16 December 2004

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 N-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.

renal hemodynamics; endothelial cell; cyclooxygenase; epoxygenase; angiotensin II; dopamine; nitric oxide; endothelin

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