Lack of nitric oxide mediation of flow-dependent arteriolar dilation in type I diabetes is restored by sepiapterin
Lack of nitric oxide mediation of flow-dependent arteriolar dilation in type I diabetes is restored by sepiapterin
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DOI：
10.1159/000068938
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发表时间：
2003-01-01
影响因子：
1.7
通讯作者：
Koller, A
中科院分区：
文献类型：
--
作者：
Bagi, Z;Koller, A
糖尿病微血管病变的发生机制目前尚不清楚。我们假设I型糖尿病影响血管内皮细胞并改变微动脉的血流依赖性扩张，这是参与局部血流调节的重要机制。与正常大鼠相比，链脲佐菌素(STZ)诱导的糖尿病大鼠分离的加压股薄肌小动脉(内径约150克，80毫米汞柱)表现出因灌流液流量增加而引起的扩张减少(血糖：25.7+/-0.7vs.6.4+/-0.5 mmol/L；最大直径增加：15+/-4vs.31+/-3um，p<；0.05)。在对照小动脉中，一氧化氮(NO)和前列腺素都介导了血流依赖性的扩张，而糖尿病小动脉的血流诱导的扩张不受N-奥米伽-硝基-L-精氨酸甲酯(L-NAME)的影响，并被消炎痛所阻断。Sepiapterin-内皮一氧化氮合酶(ENOS)辅因子四氢生物蝶呤(BH4)的前体-恢复了L名字敏感的糖尿病小动脉血流依赖性扩张部分。此外，用2，4-二氨基-6-羟基嘧啶(DAHP)阻断对照小动脉的BH_4也可降低血流依赖性的扩张，这种作用可被腔内注射的七叶蝶呤[而不是超氧化物歧化酶+过氧化氢酶(SOD+CAT)]所恢复，然后再被L-NAME所抑制。在糖尿病小动脉中，NO供体硝普钠(SNP)所致的扩张不受L-NAME的影响，而在DAHP治疗的小动脉中，内皮型一氧化氮合酶(ENOS)被血管内流激活时(有或无超氧化物歧化酶+过氧化氢酶)，均不受其影响。相比之下，焦性没食子酚(已知能产生活性氧物种)以一种超氧化物歧化酶+过氧化氢酶可逆的方式显著降低乙酰胆碱和SNP诱导的扩张。综上所述，这些发现表明，在糖尿病小动脉中，由于BH4生物利用度的降低，eNOS合成的NO受到限制，导致血流诱导的扩张减少，这一机制可能也是糖尿病微血管病变和其他血管疾病恶化的原因。版权所有(C)2003 S.Karger AG，巴塞尔。
The mechanisms leading to microangiopathy in diabetes mellitus have still not been clearly elucidated. We hypothesized that type I diabetes mellitus affects the endothelium and alters flow-dependent dilation of arterioles, an important mechanism involved in local regulation of blood flow. Isolated, pressurized gracilis muscle arterioles (inside diameter approximately 150 gm at 80 mm Hg) from rats with streptozotocin (STZ)-induced diabetes mellitus exhibited reduced dilations induced by increases in perfusate flow compared to those of normal rats (plasma glucose: 25.7 +/- 0.7 vs. 6.4 +/- 0.5 mmol/l; maximum increase in diameter: 15 +/- 4 vs. 31 +/- 3 mum, p < 0.05). In control arterioles, both nitric oxide (NO) and prostaglandins mediated the flow-dependent dilation, whereas flow-induced dilations of diabetic arterioles were unaffected by N-omega-nitro-L-arginine methyl ester (L-NAME) and were abolished by indomethacin. Sepiapterin -precursor of the endothelial NO synthase (eNOS) cofactor tetrahydrobiopterin (BH4)-restored the L-NAME-sensitive portion of flow-dependent dilations of diabetic arterioles. Furthermore, depletion of BH4 by 2,4-diamino-6-hydroxypyrimidine (DAHP) in control arterioles also resulted in reduced flow-dependent dilations, which were restored by intraluminal sepiapterin [but not with superoxide dismutase (SOD) plus catalase (CAT) (SOD+CAT)] and then could be inhibited by L-NAME. Dilations induced by the NO donor sodium nitroprusside (SNP) were unaffected by L-NAME in diabetes mellitus arterioles or when eNOS was activated by intraluminal flow in DAHP-treated arterioles (with or without SOD+CAT). In contrast, pyrogallol (known to produce reactive oxygen species) substantially reduced acetylcholine- and SNP-induced dilation in a SOD+CAT-reversible manner. Collectively, these findings suggest that in diabetic arterioles, due to the reduced bioavailability of BH4, the synthesis of NO by eNOS is limited, resulting in a reduced flow-induced dilation, a mechanism that may also be responsible for the development of diabetic microangiopathy and exacerbation of other vascular diseases. Copyright (C) 2003 S. Karger AG, Basel.