Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University, Innsbruck, Austria.
Kidney Int. 2010 Apr;77(8):681-9. doi: 10.1038/ki.2010.7. Epub 2010 Feb 17.
Tetrahydrobiopterin (BH4) is an essential cofactor for the nitric oxide (NO) synthases and represents a critical determinant of NO production. BH4 depletion during ischemia leads to the uncoupling of the synthases, thus contributing to reperfusion injury due to increased superoxide formation. To examine whether BH4 supplementation attenuates ischemia-reperfusion injury, we clamped the left renal arteries of male Lewis rats immediately following right-side nephrectomy. BH4 tissue levels significantly decreased after 45 min of warm ischemia compared with levels in non-ischemic controls. Histopathology demonstrated significant tubular damage and increased peroxynitrite formation. Intravital fluorescent microscopy found perfusion deficits in the microvasculature and leakage of the capillary mesh. Supplemental BH4 treatment before ischemia significantly reduced ischemia-induced renal dysfunction, and decreased tubular histologic injury scores and peroxynitrite generation. BH4 also significantly improved microcirculatory parameters such as functional capillary density and diameter. These protective effects of BH4 on microvasculature were significantly correlated with its ability to abolish peroxynitrite formation. We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans.
四氢生物蝶呤（BH4）是一氧化氮（NO）合酶的必需辅助因子，是 NO 生成的关键决定因素。在缺血期间 BH4 的耗竭会导致合酶解偶联，从而由于超氧化物形成增加而导致再灌注损伤。为了研究 BH4 补充是否可以减轻缺血再灌注损伤，我们在右侧肾切除术后立即夹住雄性 Lewis 大鼠的左肾动脉。与非缺血对照组相比，在 45 分钟的温热缺血后，BH4 组织水平显著降低。组织病理学显示出明显的管状损伤和过氧亚硝酸盐形成增加。活体荧光显微镜发现微血管灌注不足和毛细血管网渗漏。在缺血前进行 BH4 补充治疗可显著减轻缺血引起的肾功能障碍，并降低管状组织学损伤评分和过氧亚硝酸盐的产生。BH4 还显著改善了微血管参数，如功能毛细血管密度和直径。BH4 对微血管的这些保护作用与其消除过氧亚硝酸盐形成的能力显著相关。我们认为，BH4 可显著预防缺血再灌注后急性肾衰竭。BH4 是否具有治疗潜力将需要在人类中进行更直接的测试。
