四氢生物蝶呤（BH4），一种 nNOS 的辅助因子，可恢复雌性糖尿病大鼠的胃排空和 nNOS 表达。
Tetrahydrobiopterin (BH4), a cofactor for nNOS, restores gastric emptying and nNOS expression in female diabetic rats.
机构信息
Department of Obstetrics and Gynecology, Center for Women's Health Research, Meharry Medical College, Nashville, Tennessee 37208, USA.
出版信息
Am J Physiol Gastrointest Liver Physiol. 2010 May;298(5):G692-9. doi: 10.1152/ajpgi.00450.2009. Epub 2010 Feb 25.
Gastroparesis is a debilitating disease predominantly affecting young women. Recently, dysregulation of neuronal nitric oxide synthase (nNOS) in myenteric plexus neurons has been implicated for delayed solid gastric emptying/gastroparesis in diabetic patients. In this study, we have explored the role of tetrahydrobiopterin (BH4), a major cofactor for nNOS activity and NO synthesis in diabetic gastroparesis. Diabetes was induced with single injection of streptozotocin (55 mg/kg body wt, ip) in female rats, with experiments performed on week 3 or 9 following induction, with or without 3-wk BH4 supplementation. Gastric pyloric BH4 levels were significantly decreased in diabetic female rats compared with control (18.6 +/- 1.45 vs. 31.0 +/- 2.31 pmol/mg protein). In vitro studies showed that 2,4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor of BH4 synthesis, significantly decreased gastric NO release and nitrergic relaxation. Three-week dietary supplementation of BH4 either from day 1 or week 6 significantly attenuated diabetes-induced delayed gastric emptying for solids (3 wk: BH4, 67 +/- 6.7 vs. diabetic, 36.05 +/- 7.09; 9 wk: BH4, 57 +/- 8.45 vs. diabetic, 33 +/- 9.91) and diabetes-induced reduction in pyloric nNOS-alpha protein expression in female rats. Supplementation of BH4 significantly restored gastric nNOS-alpha dimerization in 9-wk-old diabetic female rats. In addition, BH4 treatment reversed (17.23 +/- 5.81 vs. 42.0 +/- 2.70 mmHg x s) the diabetes-induced changes in intragastric pressures (IGP) and gastric pyloric nitrergic relaxation (-0.62 +/- 0.01 vs. -0.22 +/- 0.07). BH4 deficiency plays a critical role in diabetes-induced alterations including delayed solid gastric emptying, increased IGP, reduced pyloric nitrergic relaxation, and nNOS-alpha expression in female rats. Supplementation of BH4 accelerates gastric emptying by restoring nitrergic system in diabetic female rats. Therefore, BH4 supplementation is a potential therapeutic option for female patients of diabetic gastroparesis.
胃轻瘫主要影响年轻女性，是一种使人虚弱的疾病。最近有研究表明，糖尿病患者固体胃排空延迟/胃轻瘫与肠肌丛神经元中神经元型一氧化氮合酶（nNOS）的失调有关。在这项研究中，我们探索了四氢生物蝶呤（BH4）在糖尿病性胃轻瘫中的作用，BH4 是 nNOS 活性和 NO 合成的主要辅助因子。通过链脲佐菌素（STZ）（55mg/kg 体重，ip）单次注射诱导雌性大鼠糖尿病，在诱导后 3 或 9 周进行实验，同时或不进行 3 周 BH4 补充。与对照组（18.6±1.45 对 31.0±2.31 pmol/mg 蛋白）相比，糖尿病雌性大鼠胃幽门 BH4 水平显著降低。体外研究表明，BH4 合成抑制剂 2,4-二氨基-6-羟基嘧啶（DAHP）显著降低了胃一氧化氮释放和氮能性松弛。从第 1 天或第 6 周开始，3 周的 BH4 饮食补充显著减轻了固体（3 周：BH4，67±6.7 对糖尿病，36.05±7.09；9 周：BH4，57±8.45 对糖尿病，33±9.91）和糖尿病诱导的雌性大鼠胃排空延迟，并减少了幽门 nNOS-α蛋白表达。BH4 补充显著恢复了 9 周龄糖尿病雌性大鼠的胃 nNOS-α二聚体化。此外，BH4 治疗逆转了（17.23±5.81 对 42.0±2.70mmHg×s）糖尿病诱导的胃内压（IGP）和胃幽门氮能性松弛的变化（-0.62±0.01 对-0.22±0.07）。BH4 缺乏在包括固体胃排空延迟、IGP 增加、幽门氮能性松弛减少和雌性大鼠 nNOS-α表达在内的糖尿病诱导的改变中起着关键作用。BH4 补充通过恢复糖尿病雌性大鼠的氮能系统来加速胃排空。因此，BH4 补充可能是治疗糖尿病性胃轻瘫女性患者的一种潜在治疗选择。
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