REDUCTION OF DIABETIC CARDIOVASCULAROPATHY BY AMINOGUANIDINE

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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.