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 haemodynamics appear to be mediated by activation of the AT 1 receptor subtype, AT 2 binding sites have also been evidenced in the adult kidney vasculature. As NO is known to mask part of the renal effects of vasoconstrictor drugs, we queried whether the Ang II‐induced vasoconstrictions could occur via multiple receptor subtypes during inhibition of NO synthesis. We explored the effect of AT 1 and AT 2 receptor (AT‐R) antagonists on Ang II‐induced pressure increases during NO synthase or soluble guanylyl cyclase inhibition in rat isolated kidneys perfused in the 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 n M ) antagonized the Ang II‐induced vasoconstrictions, while the AT 2 ‐R antagonist PD‐123319 (500 n M ) had no effect. 3 Perfusing kidneys in the presence of either NO synthase inhibitors, L ‐NAME (100 μ M ) or L ‐NOARG (1 m M ), or soluble guanylyl cyclase inhibitor, LY‐83583 (10 μ 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 n M L158809 abolished the Ang II‐induced vasoconstrictions whatever the concentration tested. On the other hand, 500 n M PD‐123319 reversed the left shift of the concentration–response 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 potentiated vasoconstriction induced by 0.1 n M and the augmented vasoconstriction induced by 10 n M Ang II were fully inhibited in a concentration‐dependent manner by L‐158809 (0.05–500 n M ). By contrast, PD‐123319 (0.5–500 n M ) did not affect the 10 n M Ang II‐induced vasoconstriction and concentration‐dependently decreased the 0.1 n M Ang II‐induced vasoconstriction plateauing at 65% inhibition above 5 n M antagonist. 6 Similar to PD‐123319, during NO blockade the AT 2 ‐R antagonist CGP‐42112A at 5 n M decreased by 50% the 0.1 n M Ang II‐induced vasoconstriction and at 500 n M had no effect on 10 n M Ang II‐induced vasoconstriction. 7 In conclusion, the renal Ang II‐induced vasoconstriction, which is antagonized only by AT 1 ‐R antagonist in the presence of endogenous NO, becomes sensitive to both AT 1 ‐ and AT 2 ‐R antagonists during NO synthesis inhibition. While AT 1 ‐R antagonist inhibited both L ‐NAME‐potentiated and‐augmented components of Ang II‐induced vasoconstriction, AT 2 ‐R antagonists inhibited only the L ‐NAME‐potentiated component.