Effects of Tetrahydrobiopterin on Endothelial Dysfunction in Rats with Ischemic Acute Renal Failure
J Am Soc Nephrol 11: 301–309, 2000 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, and †Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan; ‡Department of Biochemistry, Meikai University School of Dentistry, Saitama, Japan; and §Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan. Abstract. The role of nitric oxide (NO) in ischemic renal injury 4 fmol/min per g kidney; serum creatinine: control 23 Ϯ 2, is still controversial. NO release was measured in rat kidneys ischemia 150 Ϯ 27, ischemia ϩ BH4 48 Ϯ 6 M; mean Ϯ subjected to ischemia and reperfusion to determine whether SEM). Most of renal NOS activity was calcium-dependent, and (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), a cofactor of NO its activity decreased in the ischemic kidney. However, it was synthase (NOS), reduces ischemic injury. Twenty-four hours restored by BH4 (control 5.0 Ϯ 0.9, ischemia 2.2 Ϯ 0.4, after bilateral renal arterial clamp for 45 min, acetylcholine- ischemia ϩ BH4 4.3 Ϯ 1.2 pmol/min per mg protein). Immu- induced vasorelaxation and NO release were reduced and renal noblot after low-temperature sodium dodecyl sulfate-polyac- excretory function was impaired in Wistar rats. Administration rylamide gel electrophoresis revealed that the dimeric form of of BH4 (20 mg/kg, by mouth) before clamping resulted in a endothelial NOS decreased in the ischemic kidney and that it marked improvement of those parameters (10Ϫ8 M acetylcho- was restored by BH4.
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