Published Online
on October 28, 2002

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

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Submitted on June 27, 2002
Revised on August 16, 2002

Blunted Tubuloglomerular Feedback by Absence of Angiotensin Type 1A Receptor Involves Neuronal NOS

Atsuhiro Ichihara^*; Matsuhiko Hayashi; Yukako Koura; Yuko Tada; Takeshi Sugaya; Nobuhisa Hirota; and Takao Saruta

From the Department of Internal Medicine, Keio University School of Medicine (A.I., M.H., Y.K., Y.T., N.H., T. Saruta), Tokyo; and Nephrology Discovery Research Laboratory, Tanabe Seiyaku (T. Sugaya), Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: atzichi{at}sc.itc.keio.ac.jp.

Abstract—To define the role of angiotensin type 1A (AT_1A) receptor in modulating tubuloglomerular feedback signals and to determine its relationship to neuronal NO synthase (nNOS), the diameter of the afferent arterioles of wild-type and AT_1A receptor-deficient mice was measured by the blood-perfused juxtamedullary nephron technique. The afferent arteriolar diameter of wild-type and AT_1A receptor-deficient mice averaged 16.7±0.6 (n=9) and 16.8±0.7 µm (n=9), respectively. In the wild-type mice, addition of 10 µmol/L acetazolamide to the blood perfusate exerted a biphasic afferent arteriolar constriction, with the initial response and sustained response averaging 47.2±3.8% and 33.9±3.3%, respectively. In AT_1A receptor-deficient mice, the initial response and sustained response averaged 51.6±3.6% and 9.5±1.3%, respectively, and the sustained response was significantly attenuated compared with that of wild-type mice. Inhibition of nNOS with 10 µmol/L S-methyl-L-thiocitrulline significantly decreased the afferent arteriolar diameter of AT_1A receptor-deficient mice, from 15.1±1.2 to 5.0±0.3 µm (n=7), and the decrease was significantly greater than that observed in wild-type mice (from 15.9±1.2 to 10.6±1.3 µm; n=8). During nNOS inhibition, the initial and sustained afferent arteriolar constrictor responses to acetazolamide in wild-type mice averaged 54.4±6.4% and 44.8±11.3%; respectively, and were similar to those in AT_1A receptor-deficient mice (53.2±6.4% and 59.5±4.4%, respectively). These results suggest that AT_1A receptors enhance tubuloglomerular feedback-mediated afferent arteriolar constriction, at least in part, through reducing the counteracting modulation by nNOS.

Key words: arterioles • autoregulation • mice • nitric oxide synthase • receptors, angiotensin II

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