Published Online
on September 30, 2002

A more recent version of this article appeared on November 1, 2002

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Submitted on June 19, 2002
Revised on July 9, 2002

Biphasic Regulation of Na⁺-HCO₃^- Cotransporter by Angiotensin II Type 1A Receptor

Shoko Horita; Yanan Zheng; Chiaki Hara; Hideomi Yamada; Motoei Kunimi; Shigeo Taniguchi; Shu Uwatoko; Takeshi Sugaya; Atsuo Goto; Toshiro Fujita; and George Seki^*

From the Department of Internal Medicine, Faculty of Medicine, Tokyo University (S.H., Y.Z., C.H., H.Y., M.K., S.T., S.U., A.G., T.F., G.S.), Tokyo; and Discovery Research Laboratory, Tanabe Seiyaku Co Ltd (T.S.), Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: georgeseki-tky{at}umin.ac.jp.

Abstract—Although angiotensin (Ang) II is known to regulate renal proximal transport in a biphasic way, the receptor subtype(s) mediating these Ang II effects remained to be established. To clarify this issue, we compared the effects of Ang II in wild-type mice (WT) and Ang II type 1A receptor-deficient mice (AT_1A KO). The Na⁺-HCO₃^- cotransporter (NBC) activity, analyzed in isolated nonperfused tubules with a fluorescent probe, was stimulated by 10^-10 mol/L Ang II but was inhibited by 10^-6 mol/L Ang II in WT. Although valsartan (AT₁ antagonist) blocked both stimulation and inhibition by Ang II, PD 123,319 (AT₂ antagonist) did not modify these effects of Ang II. In AT_1A KO, in contrast, this biphasic regulation was lost, and only stimulation of NBC activity by 10^-6 mol/L Ang II was observed. This stimulation was blocked by valsartan but not by PD 123,319. More than 10^-8 mol/L Ang II induced a transient increase in cell Ca²⁺ concentrations in WT, which was again blocked by valsartan but not by PD 123,319. However, up to 10^-5 mol/L Ang II did not increase cell Ca²⁺ concentrations in AT_1A KO. Finally, the addition of arachidonic acid inhibited the NBC activity similarly in WT and AT_1A KO, suggesting that the inhibitory pathway involving P-450 metabolites is preserved in AT_1A KO. These results indicate that AT_1A mediates the biphasic regulation of NBC. Although low-level expression of AT_1B could be responsible for the stimulation by 10^-6 mol/L Ang II in AT_1A KO, no evidence was obtained for AT₂ involvement.

Key words: receptors, angiotensin II • renal circulation • sodium • arachidonic acids

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