Possible involvement of facilitated aldose reductase activity in the accelerated vascular remodeling in rabbits with alloxan-induced hyperglycemia

促进醛糖还原酶活性可能参与四氧嘧啶诱导的高血糖兔加速血管重塑

• 批准号: 12672209
• 负责人: AZUMA Hiroshi
• 金额: $ 1.86万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672209/
• 关键词: Aldose reductase; augmentation of intimal hvperplasia; endogenous NOS inhibitors; endothelin-1; hvperglycemia; nitric oxide; polyol pathway; sorbitol; aldose reductase inhibitor (ARI); 内膜肥厚; 内膜剥離術; endothelin-1; alloxan; polyol pathway

Present experiments were designed to investigate whether or not the facilitation of polyol pathway is involved in the augmentation of intimal hyperplasia following endothelial denudation in rabbits with alloxan-induced hyperglycemia Twelve weeks after a single bolus injection of alloxan or saline, rabbits underwent unilateral endothelial denudation of the carotid artery to cause intimal hyperplasia. An intimal hyperplasia was caused 4 weeks after the denudation and significant augmentation of the intimal hyperplasia was brought about under the hyperglycemia. The augmentation of intimal hyperplasia was accompanied by the accelerated accumulation of endogenous NOS inhibitors in regenerated endothelial cells, accelerated impairment of NO production and acceleratedaccumulation of ET-1 within the vessel wall. Sorbitol levels in aortic endothelial cells and within the vessel wall were significantly increased with hyperglycemia. All these changes which had been brought abdlit by the hyperglycemia were effectively improved by the administration offidarestat as a selective aldose reductase inhibitor for 5 weeks from 1 week before to 4 weeks after the denudation. These findings suggest that facilitation of polyol pathway possibly plays an important role for the augmentation of intimal hyperplasia with hyperglycemia.

本实验旨在研究四氧嘧啶诱导的高血糖兔内皮剥脱后多元醇途径的促进是否与内膜增生的增强有关。单次推注四氧嘧啶或盐水12周后，兔子进行单侧颈动脉内皮剥脱以引起内膜增生。剥脱后4周引起内膜增生，并且在高血糖下导致内膜增生显着增大。内膜增生的加剧伴随着再生内皮细胞中内源性NOS抑制剂的加速积累、NO生成的加速受损以及血管壁内ET-1的加速积累。主动脉内皮细胞和血管壁内的山梨醇水平随着高血糖而显着增加。剥脱前1周至剥脱后4周服用选择性醛糖还原酶抑制剂非达司他5周，可有效改善所有这些由高血糖带来的变化。这些发现表明，多元醇途径的促进可能在高血糖引起的内膜增生增强中发挥重要作用。

项目成果

Hitoshi MASUDA, Tetsuo OKUNO, Kazunori KIHARA, Hiroshi AZUMA & Toshihiko TSUJII: "Accumulated endogenous NOS inhibitors, decreased NOS activity and impaired cavernosal relaxation witn ischermia"Japanese Journal of Pharmacology. 88(Suppl. I). 248 (2002)

增田仁、奥野哲夫、木原一典、东博

: Satoshi OBAYASHI, Masashi BEPPU, Takeshi ASO, Moritaka GOTO & Hiroshi AUMA: "17β-Estradiol increases nitric oxide and prostaglandin I_2 production by cultured human uterine arteries only in histologically normal specimens"Journal of Cardiovascular Pharm

：Satoshi OBAYASHI、Masashi BEPPU、Takeshi ASO、Moritaka GOTO 和 Hiroshi AUMA：“17β-雌二醇仅在组织学正常的标本中增加培养的人子宫动脉的一氧化氮和前列腺素 I_2 的产生”心血管药学杂志

Masuda H, Okuno T, Kihara K, Azuma H, Tsujii T: "Accumulated endogenous NOS inhibitors, decreased NOS activity and impaired cavernosal relaxation with ischemia"Japanese Journal of Pharmacology. 88(Suppl.I). 248 (2002)

Masuda H、Okuno T、Kihara K、Azuma H、Tsujii T：“内源性 NOS 抑制剂累积，NOS 活性降低，缺血导致海绵体松弛受损”《日本药理学杂志》。

Beppu M,Obayashi S,Aso T,Goto M & Azuma H: "Active role of decreased NO production for increase in ET-1 and occurrence of atherosclerosis in human uterine arteries."Japanese Journal of Pharmacology. 82(SuppL I). 191P (2000)

别府 M、大林 S、麻生 T、后藤 M

Goto M,Yamauchi Y & Azuma H: "Accelerated intimal hyperplasia with hyperglycemia and its modification by an aldose reductase inhibitror"Japanese Journal of Pharmacology. 82(SuppL I)(in Press). (2001)

后藤 M、山内 Y