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1 Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Dept of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: just{at}med.unc.edu.
Vascular ETB receptors exert both dilator and constrictor actions in a complex interaction with ETA receptors. The aim of this study was to clarify the presence and relative importance of nitric oxide and other possible mechanisms underlying the dilator effects of ETB receptors in the rat kidney. Complete inhibition of NO production (L-NAME, 25 mg/kg, iv) enhanced the renal vasoconstriction elicited by entothelin-1 (ET-1) injected into the renal artery from -15 to -30%. Counteraction of the L-NAMEinduced vasoconstriction by infusion of the NO-donor nitroprusside (NP) into the renal artery did not reverse this effect (+NP=-29%), but nevertheless effectively buffered Ang II-mediated renal vasoconstriction. Similarly, renal vasoconstrictor responses to ET-1 were enhanced after a smaller dose of L-NAME administered into the renal artery (-22 vs. -15%) and unaffected by subsequent infusion of a vasodilator dose of NP (-21%). These results indicate that the responsiveness to ET-1 is buffered by endothelial ETB receptor stimulated phasic release of NO rather than the static mean ambient NO level. In other experiments, intrarenal infusion of ETB-receptor antagonist BQ788 further enhanced the constrictor response to ET-1 seen during NP + L-NAME (-92 vs. -49%), revealing a NOindependent dilator component. In controls, the vasoconstriction to ET-1 was unaffected by vehicle (-27 vs. -20%) and markedly enhanced during ETB receptor antagonism (-70%). The same pattern of ET-1 responses was observed when indomethacin was given to inhibit cyclooxygenase (control=-20%, indo=-22%, +ETB-antagonist=-56%) or MS-PPOH or Miconazole+indomethacin to inhibit epoxygenase alone (control=-10%, MSPPOH=-11%, +ETB-antag.=-35%) or in combination (control=-14%, indo+mico=-20%, +ETB-antag.=-43%). We conclude that phasic release of endogenous NO, but not the static ambient level, mediates part of the dilator effect of ETB receptors. In addition, playing a major buffering role is a NO-independent mechanism, perhaps reflecting clearance of ET by ETB receptors, that is distinct from prostanoids and epoxyeicosatrienoic acids.
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