REDUCTION OF DIABETIC CARDIOVASCULAROPATHY BY AMINOGUANIDINE

1.在胰岛素依赖型糖尿病(IDDM)大鼠中，乙酰胆碱诱导的内皮依赖性超极化和内皮衍生超极化因子(EDHF)介导的松弛功能受损。高血糖时产生的晚期糖基化终末产物(AGE)的积聚被认为不会导致EDHF功能受损。b.在IDDM患者中，毛细血管的心脏衬里迷失方向。微血管定向障碍被认为是由于胰岛素缺乏引起的纤溶酶原激活物抑制物-1(PAI-1)降低所致的高纤溶状态所致。C.缓激肽诱导的内皮源性松弛因子(EDRF)介导的冠脉血管床扩张受到损害，而EDHF介导的扩张作用不受影响。胰岛素依赖型糖尿病心脏存在微血管定向障碍和微血管定向障碍，提示IDDM心脏存在微血管定向障碍和EDRF多功能等微血管病变。微血管病变的机制可能与低PAI-1引起的纤溶亢进有关，由于我们在体外已发现胰岛素增加培养的大鼠冠状动脉微血管内皮细胞PAI-1的蛋白表达，因此胰岛素缺乏可导致体内冠状动脉微血管内PAI-1的降低。下一步需要进一步研究胰岛素、PAI-1和组织型纤溶酶原激活物之间的关系，以澄清这一假说。此外，在本研究中，临床上可用的抗溃疡药物伊索拉定抑制了微血管病变。如果抑制微血管病变改善了IDDM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.