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 controversi al. NO release was measured in rat kidneys subjected to ischemia and reperf usion to determine whether (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), a cof actor of NO synthase (NOS), reduces ischemic injury. Twenty-four hours afte r bilateral renal arterial clamp for 45 min, acetylcholine-induced vasorela xation and NO release were reduced and renal excretory function was impaire d in Wistar rats. Administration of BH4 (20 mg/kg, by mouth) before clampin g resulted in a marked improvement of those parameters (10(-8) M acetylchol ine, Delta renal perfusion pressure: sham-operated control -45 +/- 5, ische mia -30 +/- 2, ischemia + BH4 -43 +/- 4%; Delta NO: control +30 +/- 6, isch emia +10 +/- 2, ischemia + BH4 +23 +/- 4 fmol/min per g kidney; serum creat inine: control 23 +/- 2, ischemia 150 +/- 27, ischemia + BH4 48 +/- 6 mu M; mean +/- SEM). Most of renal NOS activity was calcium-dependent, and its a ctivity 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 sulfat e-polyacrylamide gel electrophoresis revealed that the dimeric form of endo thelial NOS decreased in the ischemic kidney and that it was restored by BH 4. 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.