AT2 antagonist‐sensitive potentiation of angiotensin II‐induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature
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Media type:
E-Article
Title:
AT2 antagonist‐sensitive potentiation of angiotensin II‐induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature
Description:
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<jats:list-item><jats:p>We showed earlier that NO inhibition caused a left‐shift and augmented E<jats:sub>max</jats:sub> of the concentration‐response curve of AT<jats:sub>1</jats:sub>‐mediated (angiotensin II)‐induced vasoconstrictions (AII‐VC) in the rat kidney. The 0.01–0.1 n<jats:sc>M</jats:sc> AII‐VC unmasked by the potentiating effect of NO inhibition, were sensitive not only to AT<jats:sub>1</jats:sub> (L158809), but also to AT<jats:sub>2</jats:sub> receptor (PD123319) antagonists. We now demonstrate the role of endothelium and eicosanoids in the NO‐masked AT<jats:sub>1</jats:sub>/AT<jats:sub>2</jats:sub>‐mediated component of the AII‐VC in isolated indomethacin‐perfused kidneys of the rat.</jats:p></jats:list-item>
<jats:list-item><jats:p><jats:sc>L</jats:sc>‐NAME increased 0.1 n<jats:sc>M</jats:sc> AII‐VC 7.2 fold. Pretreatment of the kidneys with factor VIII antibody/complement or with the detergent CHAPS to damage endothelium, decreased carbachol‐induced vasodilatation and blunted by 60 and 30% respectively, the enhancement of AII‐VC during NO inhibition.</jats:p></jats:list-item>
<jats:list-item><jats:p><jats:sc>L</jats:sc>‐NAME also increased 3 μ<jats:sc>M</jats:sc> noradrenaline (NA)‐induced vasoconstriction (NA‐VC) 8.1 fold. In contrast to AII‐VC, endothelium damage was without effect on the enhancement of NA‐VC by <jats:sc>L</jats:sc>‐NAME, suggesting a dominant role of endothelium‐derived NO in the enhancement of NA‐VC.</jats:p></jats:list-item>
<jats:list-item><jats:p>During NO inhibition, ETYA (2 μ<jats:sc>M</jats:sc>; an inhibitor of all arachidonic acid derived pathways) and α‐naphtoflavone (10 μ<jats:sc>M</jats:sc>; an inhibitor of the cytochrome P450 isozymes), decreased by 85% the 0.1 n<jats:sc>M</jats:sc> AII‐VC.</jats:p></jats:list-item>
<jats:list-item><jats:p>In conclusion, during NO inhibition, the AT<jats:sub>1</jats:sub>‐mediated constriction to low concentrations of AII, which is sensitive to AT<jats:sub>2</jats:sub> antagonists, depends on intact endothelium, and can be blocked by inhibition of eicosanoid synthesis. The results suggest that the AII‐mediated vasoconstriction through AT<jats:sub>1</jats:sub> receptors is potentiated in the absence of NO, by the release of eicosanoids from the endothelium through AT<jats:sub>2</jats:sub> receptors.</jats:p></jats:list-item>
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