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(Hypertension. 2003;42:600.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Angiotensin AT₂ Receptors Directly Stimulate Renal Nitric Oxide in Bradykinin B₂-Receptor–Null Mice

From the Department of Medicine, University of Virginia School of Medicine, Charlottesville.

Correspondence to Helmy M. Siragy, MD, Department of Internal Medicine, Box 801409, University of Virginia Health System, 450 Ray C. Hunt Dr, Charlottesville, VA 22908. E-mail hms7a{at}virginia.edu

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 B₂-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 B₂-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 AT₂-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 B₂ receptor.

Key Words: nitric oxide • receptors, angiotensin II • animals, transgenic • receptors, bradykinin • angiotensin II • cyclic GMP

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