REDUCTION OF DIABETIC CARDIOVASCULAROPATHY BY AMINOGUANIDINE

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）的积累并不被认为是导致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。

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.