REDUCTION OF DIABETIC CARDIOVASCULAROPATHY BY AMINOGUANIDINE

氨基胍减少糖尿病心血管病

• 批准号: 06670683
• 负责人: SAKUMA Ichiro
• 金额: $ 1.41万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670683/
• 关键词: Diabetes mellitus; Aminoguanidine; Endothelium-derived hyperpolarizing factor; Insulin; Acetylcholine; Advanced glycosylation endproduct; Coronary microvasculopathy; Plasminoge activator inhibitor-1; advanced glycosylation endproduct; 心臓; β交感神経

a.In rat with insulin-dependent diabetes mellitus (IDDM) acetylcholin-induced endothelium-dependent hyperpolarization and relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) were impaired. Accumulation of advanced glycosylation endproduct (AGE) generated in hyperglycemia was not thought to result in the impaired EDHF function.b.In IDDM heart lining of capillary vessels was disorientated. The microvascular disorientation was thought to derive from hyperfibrinolytic state due to low plasminogen activator inhibitor-1 (PAI-1) resulting from insulin deficiency. AGE was not thought to be related to the microvasculopathy.c.Bradykinin-induced dilatation of coronary vascular beds mediated by endothelium-derived relaxing factor (EDRF), but not that by EDHF,was impaired. The impaired EDRF function was reduced by normalizing hyperfibrinolysis and the resultant microvasculular disorientation with irsogladine.Thus, it was revealed that microvasculopathy such as microvascular disorientation and EDRF mulfunction exists in the IDDM heart. The mechanisms of microvasculopathy were presumably related to hyperfibrinolysis resutling from low PAI-1 ; since we had found in vitro that insulin increases PAI-1 protein in cultured rat coronary capillary endothelial cells, the lack of insulin in IDDM could lead to low PAI-1 in coronary microvessels in vivo. In the next step to clarify the hypothesis, the relationship among insulin, PAI-1 and tissue plasminogen activator should be investigated further in detail. In addition, in the present study irsogladine, a clinically available antiulcer drug, inhibited the microvasculopathy. If the inhibition of microvasculopathy improves cardiac function in IDDM heart, irsogladine may be clinically of great value.

在胰岛素依赖型糖尿病（insulin-dependent diabetes mellitus，IDDM）大鼠，乙酰胆碱诱导的内皮依赖性超极化和内皮源性超极化因子（endothelium-derived hyperpolarizing factor，EDHF）介导的舒张功能受损。高血糖时产生的晚期糖基化终产物（AGE）的积累不被认为是导致EDHF功能受损的原因。B.在IDDM中，毛细血管的心脏衬里被打乱。微血管定向障碍被认为是由于胰岛素缺乏导致纤溶酶原激活物抑制物-1（派-1）水平降低而导致纤溶亢进。AGE被认为是不相关的微血管病变。c.缓激肽诱导的扩张冠状动脉血管床介导的内皮源性舒张因子（EDRF），但不是由EDHF，受损。用Irsogladine使纤维蛋白溶解亢进和微血管定向障碍正常化，从而使受损的EDRF功能降低，从而揭示了微血管病变如微血管定向障碍和EDRF功能障碍在IDDM心脏中的存在。微血管病变的发生机制可能与派-1水平降低导致纤溶功能亢进有关，由于我们在体外培养的大鼠冠状动脉毛细血管内皮细胞中发现胰岛素可增加派-1蛋白，因此在体内实验中，胰岛素缺乏可导致IDDM患者冠状动脉微血管派-1水平降低。在下一步阐明这一假说时，胰岛素、派-1和组织型纤溶酶原激活剂之间的关系应进一步详细研究。此外，在本研究中，临床上可用的抗溃疡药物irsogladine可抑制微血管病变。如果微血管病变的抑制能改善胰岛素依赖型糖尿病心脏的心功能，伊索拉定可能具有重要的临床价值。

项目成果

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Mitsuhiro Fukao et al.: "Structural defferences in the ability of lysophospholipids to inhibit endothelium-dependent hyperpolarization by acetylcholine in rat mesenteric artery" Biochem Biophys Res Commun. 227. 479-483 (1996)

Mitsuhiro Fukao 等人：“大鼠肠系膜动脉中溶血磷脂抑制乙酰胆碱依赖的内皮细胞超极化能力的结构差异”Biochem Biophys Res Commun。

Michio Hashimoto et al.: "Note on the acetylcholine-induced relaxation of porcine coronary arteries" Life Sciences. 54. 525-531 (1994)

Michio Hashimoto 等人：“关于乙酰胆碱诱导的猪冠状动脉松弛的注意事项”生命科学。

Mitsuhiro Fukao et al.: "Thapsigargin-and cyclopiazonic acid-induced eudothelium-dependeut hyperpolarization in rat mesenteric artery." British Journal of Pharwacology. 115. 987-992 (1995)

Mitsuhiro Fukao 等人：“毒胡萝卜素和环吡嗪酸诱导大鼠肠系膜动脉内皮依赖性超极化。”

Risa Korenaga: "Laminar flow stimulates ATP-and shear stress-dependent nitric oxide production in cultured bovine endothelial cells." Biochem Biophys Res Commun. 198. 213-219 (1994)

Risa Korenaga：“层流刺激培养的牛内皮细胞中 ATP 和剪切应力依赖性一氧化氮的产生。”