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

Both bradykinin B₂ and angiotensin II type 2 (AT₂) receptors are known to stimulate renal production of nitric oxide (NO). To evaluate the individual contributions of AT₂ and B₂ receptors to renal NO production, we monitored renal interstitial, stable NO metabolites and cGMP by a microdialysis technique in conscious, bradykinin B₂-null and wild-type mice (n=8 in each group) during low sodium intake alone or with the angiotensin AT₁ or AT₂ receptor blockers, valsartan (0.5 μg/min) or PD123319 (0.15 μg/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 B₂-null mice but to a significantly greater degree in the wild-type than in B₂-null mice. PD123319 decreased NO and cGMP in both wild-type and B₂-null mice. Combined valsartan and PD123319 decreased NO and cGMP in both wild-type and B₂-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-B₂ receptor cascade. Blockade of the AT₁ receptor enhances the production of NO via the AT₂ receptor in both wild-type and B₂-null mice. We conclude that NO can be produced by 2 alternative pathways: directly through the AT₂ receptor or indirectly from AT₂ receptor stimulation of bradykinin via the B ₂ receptor.