PATHOGENETIC MECHANISMS IN DIABETIC VASCULAR DISEASE

我的研究计划的长期目标是阐明 糖尿病晚期并发症的发病机制。 几行 有证据表明，许多（如果不是全部）代谢失衡 目前与糖尿病的早期血管和神经并发症有关 或者是葡萄糖诱导的代谢的结果， 缺氧（“高血糖性缺氧”），即，的比率的增加 NADH/NAD+，尽管正常组织p02。 以前的研究已经建立了 增加山梨糖醇氧化为果糖， NAD+还原为NADH，与增加的 乳酸/丙酮酸（细胞溶质比的可靠参数， NADH/NAD+）和增加的血流量和血管通透性。 这些 氧化还原变化和血管功能障碍与相应的 缺血/缺氧心肌的变化以及氧化还原和血管变化 与氰化物中毒有关 有几条证据支持 假设这些氧化还原变化可能引发合成增加 一氧化氮（NO）是一种强有力的血管扩张剂，可介导血管紧张素转换酶的活性， 与这三种疾病有关的功能障碍。 具体 本提案中概述的实验目的是：（1）阐明 NO生成增加在糖尿病发病机制中的作用 并发症，（2）评估氨基胍，一种新的 发现了新的一氧化氮合酶抑制剂，通过 糖酵解和山梨醇途径，和（3）调查的影响， 升高的葡萄糖水平和山梨醇途径代谢对NO合成的影响 L-精氨酸。 在无细胞提取物和无细胞提取物中无合酶活性。 体外培养的组织将通过L- [胍基14 C]-精氨酸转换为L-瓜氨酸，测量cGMP水平，以及 测量NO2（NO的氧化产物）。 的潜在 这项研究的意义在于，它可能提供的见解 关于糖尿病晚期并发症的发病机制， 有助于制定新的预防和 糖尿病并发症的治疗。

The long range goal of my research program is to elucidate the pathogenesis of the late complications of diabetes. Several lines of evidence indicate that many, if not all, of the metabolic imbalances currently linked to early vascular and neural complications of diabetes either contribute to or are the consequence of glucose-induced metabolic hypoxia ("hyperglycemic hypoxia"), i.e., an increase in the ratio of NADH/NAD+ despite normal tissue p02. Previous studies have established that increased oxidation of sorbitol to fructose, which is coupled to reduction of NAD+ to NADH, is associated with an increased ratio of lactate/pyruvate (a reliable parameter of the cytosolic ratio of NADH/NAD+) and increased blood flow and vascular permeability. These redox changes and vascular dysfunction are similar to corresponding changes in ischemic/hypoxic myocardium and to redox and vascular changes associated with cyanide poisoning. Several lines of evidence support the hypothesis that these redox changes may initiate increased synthesis of nitric oxide (NO), a potent vasodilator, which could mediate the vascular dysfunction associated with all three of these conditions. The specific aims of the experiments outlined in this proposal are to: (1) elucidate the role of increased NO production the pathogenesis of diabetic complications, (2) assess the effects of aminoguanidine, a newly discovered novel inhibitor of NO synthase, on metabolism of glucose via glycolysis and the sorbitol pathway, and (3) investigate the effects of elevated glucose levels and sorbitol pathway metabolism on NO synthesis from L-arginine. No synthase activity in cell free extracts and in tissues incubated in vitro will be monitored by the conversion of L- [guanidino14 C]-arginine to L-citrulline, measurement of cGMP levels, and measurement of NO2 (an oxidation product of NO). The potential significance of this research is that the insights it may provide regarding the pathogenesis of late complications of diabetes may contribute to the development of new approaches for the prevention and treatment of diabetic complications.