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

1 We showed earlier that NO inhibition caused a left-shift and augment ed E-max of the concentration-response curve of AT(1)-mediated (angiot ensin 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 AT(1) (L158809), but also to AT(2) recepto r (PD123319) antagonists. We now demonstrate the role of endothelium a nd eicosanoids in the NO-masked AT(1)/AT(2)-mediated component of the AII-VC in isolated indomethacin-perfused kidneys of the rat. 2 L-NAME increased 0.1 nM AU-VC 7.2 fold. Pretreatment of the kidneys with fact or VIII antibody/ complement or with the detergent CHAPS to damage end othelium, 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 mu M noradrenaline (NA)-induced vasoconstri ction (NA-VC) 8.1 fold. In contrast to AII-VC, endothelium damage was without effect on the enhancement of NA-VC by LNAME, suggesting a domi nant role of endothelium-derived NO in the enhancement of NA-VC. 4 Dur ing NO inhibition, ETYA (2 mu M; an inhibitor of all arachidonic acid derived pathways) and alpha-naphtoflavone (10 mu M; an inhibitor of th e 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 AT(2) antagonists, depen ds on intact endothelium, and can be blocked by inhibition of eicosano id synthesis. The results suggest that the AII-mediated vasoconstricti on through ATI receptors is potentiated in the absence of NO, by the r elease of deicosanoids from the endothelium through AT(2) receptors.