Effects of tetrahydrobiopterin on endothelial dysfunction in rats with ischemic acute renal failure.
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.
Kakoki
Masao
M
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Hirata
Yasunobu
Y
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Hayakawa
Hiroshi
H
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Suzuki
Etsu
E
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Nagata
Daisuke
D
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Tojo
Akihiro
A
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Nishimatsu
Hiroaki
H
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Nakanishi
Nobuo
N
Department of Biochemistry, Meikai University School of Dentistry, Saitama, Japan.
Hattori
Yoshiyuki
Y
Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan.
Kikuchi
Kazuya
K
Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Nagano
Tetsuo
T
Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Omata
Masao
M
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
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
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