AT₂ antagonist-sensitive potentiation of angiotensin II-induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature

Abstract

1. We showed earlier that NO inhibition caused a left-shift and augmented E_max of the concentration-response curve of AT₁-mediated (angiotensin II)-induced vasoconstrictions (AII-VC) in the rat kidney. The 0.01–0.1 nM AII-VC unmasked by the potentiating effect of NO inhibition, were sensitive not only to AT₁ (L158809), but also to AT₂ receptor (PD123319) antagonists. We now demonstrate the role of endothelium and eicosanoids in the NO-masked AT₁/AT₂-mediated component of the AII-VC in isolated indomethacin-perfused kidneys of the rat.

2. L-NAME increased 0.1 nM 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.

3. L-NAME also increased 3 μM 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 L-NAME, suggesting a dominant role of endothelium-derived NO in the enhancement of NA-VC.

4. During NO inhibition, ETYA (2 μM; an inhibitor of all arachidonic acid derived pathways) and α-naphtoflavone (10 μM; an inhibitor of the cytochrome P450 isozymes), decreased by 85% the 0.1 nM AII-VC.

5. In conclusion, during NO inhibition, the AT₁-mediated constriction to low concentrations of AII, which is sensitive to AT₂ antagonists, depends on intact endothelium, and can be blocked by inhibition of eicosanoid synthesis. The results suggest that the AII-mediated vasoconstriction through AT₁ receptors is potentiated in the absence of NO, by the release of eicosanoids from the endothelium through AT₂ receptors.

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