AT(2)-ANTAGONIST SENSITIVE POTENTIATION OF ANGIOTENSIN-II-INDUCED VASOCONSTRICTIONS BY BLOCKADE OF NITRIC-OXIDE SYNTHESIS IN RAT RENAL VASCULATURE

1 Although the actions of angiotensin II (Ang II) on renal haemodynami cs appear to be mediated by activation of the AT(1) receptor subtype, AT(2) binding sites have also been evidenced in the adult kidney vascu lature. As NO is known to mask part of the renal effects of vasoconstr ictor drugs, we queried whether the Ang II-induced vasoconstrictions c ould occur via multiple receptor subtypes during inhibition of NO synt hesis. We explored the effect of AT(1) and AT(2) receptor (AT-R) antag onists on Ang II-induced pressure increases during NO synthase or solu ble guanylyl cyclase inhibition in rat isolated kidneys perfused in th e presence of indomethacin at constant flow in a single-pass circuit. 2 In the absence of NO blockade, the AT(1)-R antagonist L-158809 (500 nM) antagonized the Ang II-induced vasoconstrictions, while the AT(2)- R antagonist PD-123319 (500 nM) had no effect. 3 Perfusing kidneys in the presence of either NO synthase inhibitors, L-NAME (100 mu M) or L- NOARG (1 mM), or soluble guanylyl cyclase inhibitor, LY-83583 (10 mu M ), significantly increased both molar pD(2) (from 9.40+/-0.25 to 10.36 +/-0.11) and E-max values (from 24.9+/-3.1 to 79.9+/-4.9 mmHg) of the concentration-response curve for Ang II-induced vasoconstriction. 4 In the presence of L-NAME, 500 nM L158809 abolished the Ang II-induced v asoconstrictions whatever the concentration tested. On the other hand, 500 nM PD-123319 reversed the left shift of the concentration-respons e curve for Ang II (molar pD(2) value 9.72+/-0.13) leaving E-max value unaffected (91.3+/-7.6 mmHg). 5 In the presence of L-NAME, the potent iated vasoconstriction induced by 0.1 nM and the augmented vasoconstri ction induced by 10 nM Ang II were fully inhibited in a concentration- dependent manner by L-158809 (0.05-500 nM). By contrast, PD-123319 (0. 5-500 nM) did not affect the 10 nM Ang II-induced vasoconstriction and concentration-dependently decreased the 0.1 nM Ang II-induced vasocon striction plateauing at 65% inhibition above 5 nM antagonist. 6 Simila r to PD-123319, during NO blockade the AT(2)-R antagonist CGP-42112A a t 5 nM decreased by 50% the 0.1 nM Ang II-induced vasoconstriction and at 500 nM had no effect on 10 nM Ang II-induced vasoconstriction. 7 I n conclusion, the renal Ang II-induced vasoconstriction, which is anta gonized only by AT(1)-R antagonist in the presence of endogenous NO, b ecomes sensitive to both AT(1)- and AT(2)-R antagonists during NO synt hesis inhibition. While AT(1)-R antagonist inhibited both L-NAME-poten tiated and -augmented components of Ang II-induced vasoconstriction, A T(2)-R antagonists inhibited only the L-NAME-potentiated component.