Published Online
on September 2, 2003

A more recent version of this article appeared on October 1, 2003

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Submitted on June 11, 2003
Revised on July 7, 2003

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

Peter M. Abadir; Robert M. Carey; and Helmy M. Siragy^*

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

^* To whom correspondence should be addressed. E-mail: hms7a{at}virginia.edu.

Abstract--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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