AT 2 antagonist‐sensitive potentiation of angiotensin II‐induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature

We showed earlier that NO inhibition caused a left‐shift and augmented E max of the concentration‐response curve of AT 1 ‐mediated (angiotensin II)‐induced vasoconstrictions (AII‐VC) in the rat kidney. The 0.01–0.1 n M AII‐VC unmasked by the potentiating effect of NO inhibition, were sensitive not only to AT 1 (L158809), but also to AT 2 receptor (PD123319) antagonists. We now demonstrate the role of endothelium and eicosanoids in the NO‐masked AT 1 /AT 2 ‐mediated component of the AII‐VC in isolated indomethacin‐perfused kidneys of the rat.L ‐NAME increased 0.1 n M 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.L ‐NAME also increased 3 μ M 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. During NO inhibition, ETYA (2 μ M ; an inhibitor of all arachidonic acid derived pathways) and α‐naphtoflavone (10 μ M ; an inhibitor of the cytochrome P450 isozymes), decreased by 85% the 0.1 n M AII‐VC. In conclusion, during NO inhibition, the AT 1 ‐mediated constriction to low concentrations of AII, which is sensitive to AT 2 antagonists, depends on intact endothelium, and can be blocked by inhibition of eicosanoid synthesis. The results suggest that the AII‐mediated vasoconstriction through AT 1 receptors is potentiated in the absence of NO, by the release of eicosanoids from the endothelium through AT 2 receptors.