title: Effects of tetrahydrobiopterin on endothelial dysfunction in rats with ischemic acute renal failure.
abstract: 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, delta renal perfusion pressure: sham-operated control -45 +/- 5, ischemia -30 +/- 2, ischemia + BH4 -43 +/- 4%; delta 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 microM; 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.
authors.affiliation: The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kakoki
authors.affiliation: The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hayakawa
authors.affiliation: The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Etsu
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagata
authors.affiliation: The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tojo
authors.affiliation: The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.affiliation: Department of Biochemistry, Meikai University School of Dentistry, Saitama, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nakanishi
authors.affiliation: Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.affiliation: The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D007511:Ischemia / Q000150:complications* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000503:physiopathology
chemical_list: D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C003402:sapropterin