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Inducible Nitric Oxide Synthase Attenuates Endothelium-Dependent Renal Microvascular Vasodilation

ATSUHIRO ICHIHARA^*,, MATSUHIKO HAYASHI^*, L. GABRIEL NAVAR and TAKAO SARUTA^*

^* Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana.

Correspondence to Dr. Takao Saruta, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Phone: +81-3-5363-3796; Fax: +81-3-3359-2745; E-mail: saruta{at}med.keio.ac.jp

Abstract. Previous studies have demonstrated that inducible nitric oxide synthase (iNOS) plays a key pathophysiologic role during sepsis. The present study was designed to delineate the consequences of iNOS activation on renal microvascular function. Male Sprague-Dawley rats were given intraperitoneal injections of lipopolysaccharide (LPS; 4 mg/kg) at 16 h and 4 h before experimentation. Afferent and efferent arteriolar diameters from LPS-treated and control rats were assessed in vitro with the use of the blood perfused juxtamedullary nephron technique. Basal afferent and efferent arteriolar diameters of LPS-treated rats averaged 19.7 ± 0.9 (n = 7) and 18.3 ± 1.0 µm (n = 5), respectively, and were similar to those of control rats (20.8 ± 0.3 [n = 6] and 18.4 ± 0.6 µm [n = 6], respectively). Superfusion with the selective iNOS inhibitor S,S'-(1,3-phenylenebis[1,2-ethanediyl]) bisisothiourea (PBIT), at the doses of 0.01, 0.1, and 1 µM, significantly decreased afferent and efferent arteriolar diameters in a dose-dependent manner, whereas afferent or efferent arteriolar diameters of control rats were not altered in response to the same doses of PBIT. In the second series of experiments, superfusion with 10 µM acetylcholine (ACh) significantly increased afferent and efferent arteriolar diameters of LPS-treated rats by 14.9 ± 1.6% (n = 9) and 6.6 ± 1.1% (n = 6), respectively. The ACh-induced afferent and efferent arteriolar dilator responses were inhibited by superfusion with the nonselective NOS inhibitor N-nitro-L-arginine (100 µM). However, afferent and efferent arteriolar dilator responses to ACh were significantly enhanced during selective iNOS inhibition with 1 µM PBIT (40.1 ± 0.7% and 25.2 ± 1.3%, respectively). These results suggest that activation of iNOS by LPS increases the influence of nitric oxide on afferent and efferent arteriolar tone and impairs endothelium-dependent nitric oxide effects.

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