Angiotensin AT ₂ Receptors Directly Stimulate Renal Nitric Oxide in Bradykinin B ₂ -Receptor–Null Mice

Abstract

Abstract-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 (nϭ8 in each group) during low sodium intake alone or with the angiotensin AT 1 or AT 2 receptor blockers, valsartan (0.5 g/min) or PD123319 (0.15 g/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 AT 1 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 Key Words: nitric oxide Ⅲ receptors, angiotensin II Ⅲ animals, transgenic Ⅲ receptors, bradykinin Ⅲ angiotensin II Ⅲ cyclic GMP P revious studies demonstrated that angiotensin II type 1 (AT 1 ) receptor blockade increases renal nitric oxide (NO) and that this increase is abolished by angiotensin II type 2 (AT 2 ) receptor blockade, proving that the AT 2 receptor is responsible for the increase in NO. 1,2 Similarly, activation of the AT 2 receptor results in an increase in renal cGMP. 3 Because cGMP functions as a second messenger for NO, its increase in response to AT 2 receptor stimulation is thought to be mediated by NO 3 . Furthermore, AT 2 receptor stimulation increases renal bradykinin (BK), 4,5 which in turn increases NO production. 6 Thus, previous studies demonstrated that the AT 2 receptor mediates a vasodilator 5 cascade that includes BK, NO, and cGMP. These observations raise the question as to whether BK is an obligatory intermediate in the putative BK-NO-cGMP signaling cascade mediated by the AT 2 receptor.BK, the major effector hormone of the kallikrein-kinin system, acts mainly through the BK B 2 -subtype (B 2 ) receptor to mediate the majority of its cardiovascular and renal actions. 7 Studies in mice that lack the B 2 receptor (B 2 -/-) have reported normal development, blood pressure, and renal function. 8 -10 It is not known how B 2 -/-mice produce NO to maintain their normal blood pressures.In the present study, we investigated whether the AT 2 receptor can directly stimulate renal NO prod...

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