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Effects of Tetrahydrobiopterin on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure

MASAO KAKOKI^*, YASUNOBU HIRATA^*, HIROSHI HAYAKAWA^*, ETSU SUZUKI^*, DAISUKE NAGATA^*, AKIHIRO TOJO^*, HIROAKI NISHIMATSU^*, NOBUO NAKANISHI, YOSHIYUKI HATTORI^§, KAZUYA KIKUCHI, TETSUO NAGANO and MASAO OMATA^*

^* The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
Department of Biochemistry, Meikai University School of Dentistry, Saitama, Japan
^§ Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan

Correspondence to Dr. Yasunobu Hirata, The Second Department of Internal Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: +81-3-5800-8649; Fax: +81-3-3814-0021; E-mail: hirata-2im{at}h.u-tokyo.ac.jp

The role of nitric oxide (NO) in ischemic renal injury is still controversial. NO release was measured in rat kidneys subjected to ischemia and reperfusion to determine whether (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), a cofactor of NO synthase (NOS), reduces ischemic injury. Twenty-four hours after bilateral renal arterial clamp for 45 min, acetylcholine-induced vasorelaxation and NO release were reduced and renal excretory function was impaired in Wistar rats. Administration of BH4 (20 mg/kg, by mouth) before clamping resulted in a marked improvement of those parameters (10^-8 M acetylcholine, renal perfusion pressure: sham-operated control -45 ± 5, ischemia -30 ± 2, ischemia + BH4 -43 ± 4%; NO: control +30 ± 6, ischemia +10 ± 2, ischemia + BH4 +23 ± 4 fmol/min per g kidney; serum creatinine: control 23 ± 2, ischemia 150 ± 27, ischemia + BH4 48 ± 6 µM; mean ± SEM). Most of renal NOS activity was calcium-dependent, and its activity decreased in the ischemic kidney. However, it was restored by BH4 (control 5.0 ± 0.9, ischemia 2.2 ± 0.4, ischemia + BH4 4.3 ± 1.2 pmol/min per mg protein). Immunoblot after low-temperature sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the dimeric form of endothelial NOS decreased in the ischemic kidney and that it was restored by BH4. These results suggest that the decreased activity of endothelium-derived NO may worsen the ischemic tissue injury, in which depletion of BH4 may be involved.

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