Angiotensin AT2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice

Both bradykinin B-2 and angiotensin II type 2 (AT(2)) receptors are known to stimulate renal production of nitric oxide ( NO). To evaluate the individual contributions of AT(2) and B-2 receptors to renal NO production, we monitored renal interstitial, stable NO metabolites and cGMP by a microdialysis technique in conscious, bradykinin B-2-null and wild-type mice (n = 8 in each group) during low sodium intake alone or with the angiotensin AT(1) or AT(2) receptor blockers, valsartan (0.5 mug/min) or PD123319 (0.15 mug/min), or both. During normal salt intake, renal interstitial fluid NO and cGMP levels in B-2-null mice were not different from those of wild-type mice. Low sodium intake increased NO and cGMP in wild-type mice but not in B-2-null mice. Valsartan increased NO and cGMP in both wild-type and B-2-null mice but to a significantly greater degree in the wild-type than in B-2-null mice. PD123319 decreased NO and cGMP in both wild-type and B-2-null mice. Combined valsartan and PD123319 decreased NO and cGMP in both wild-type and B-2-null mice, but there was no significant difference during combined treatment from their levels after administration of PD123319 alone. Our results indicate that during ingestion of a low-salt diet, production of NO is mediated mainly via the AT(2)-B-2 receptor cascade. Blockade of the AT1 receptor enhances the production of NO via the AT(2) receptor in both wild-type and B-2-null mice. We conclude that NO can be produced by 2 alternative pathways: directly through the AT(2) receptor or indirectly from AT(2) receptor stimulation of bradykinin via the B-2 receptor.