ACE inhibitor and prevention of diabetic retinopathy

描述（由申请人提供）：几项临床研究检测到ACE（血管紧张素转换酶）抑制剂对糖尿病视网膜病变的意外抑制作用，但该作用的机制尚不清楚。有证据表明，高血糖的严重程度是视网膜病变的发病机制中的一个主要的起始因素，我们已经检查了血管紧张素转换酶抑制剂卡托普利对糖尿病大鼠视网膜中葡萄糖水平的影响。我们的初步数据表明，卡托普利抑制糖尿病诱导的葡萄糖在糖尿病大鼠视网膜的积累。同样地，在葡萄糖浓度升高的条件下培养的视网膜细胞中，卡托普利显著抑制细胞内葡萄糖蓄积，表明视网膜组织中葡萄糖蓄积的抑制不仅仅是由于血压或血管通透性的降低。当细胞内葡萄糖升高时可在细胞内产生的山梨醇在糖尿病视网膜中同样增加，并被卡托普利抑制，进一步证明了在糖尿病大鼠视网膜中葡萄糖在细胞内升高，并且卡托普利抑制葡萄糖的积累。这些结果表明，ACE抑制剂对糖尿病视网膜病变的发展的有益作用可能部分来自于抑制视网膜中细胞内葡萄糖的积累，从而限制高血糖代谢后遗症的激活。该项目将确定糖尿病视网膜中葡萄糖蓄积的抑制是否是一般抗高血压药物的特征，或者是一类抗高血压药物或一种药物所特有的，并研究ACE抑制剂抑制细胞内葡萄糖蓄积的机制。 葡萄糖蓄积的抑制代表了ACE抑制剂对糖尿病视网膜病变发展的有益作用的新机制。我们认为，具有这种作用的药物可以被表征和改进，提供了一种额外的药理学手段来抑制糖尿病视网膜病变的发展和进展。

DESCRIPTION (provided by applicant): Several clinical studies have detected an unexpected inhibition of diabetic retinopathy by ACE (angiotensin-converting enzyme) inhibitors, and the mechanism for this action is unclear. In light of evidence indicating that the severity of hyperglycemia is a major initiating factor in the pathogenesis of retinopathy, we have examined the effect of ACE inhibitor captopril on glucose level in the retina of diabetic rats. Our preliminary data suggest that captopril inhibits diabetes-induced accumulation of glucose in the retina of diabetic rats. Likewise, captopril significantly inhibits intracellular glucose accumulation in retinal cells cultured in elevated glucose concentration, indicating that inhibition of glucose accumulation in retinal tissue is not due solely to reduction in blood pressure or in vascular permeability. Sorbitol, which can be produced within cells when intracellular glucose is elevated, likewise is increased in the retina in diabetes, and inhibited by captopril, further demonstrating that glucose is elevated intracellularly in the retina of diabetic rats and that captopril inhibits the accumulation of glucose. These findings suggest the overall hypothesis that beneficial effects of ACE inhibitors on the development of diabetic retinopathy might result in part from inhibition of intracellular glucose accumulation in retinas, thus restricting the activation of metabolic sequelae of hyperglycemia. The proposed project is going to determine if inhibition of glucose accumulation in the diabetic retina is characteristic of antihypertensive medications in general, or is unique to one class of antihypertensive drugs, or to one drug and to investigate the mechanism by which the ACE inhibitor inhibits intracellular glucose accumulation. Inhibition of glucose accumulation represents a novel mechanism for the observed beneficial effect of ACE inhibitors on the development of diabetic retinopathy. We believe that agents having this effect can be characterized and improved, offering an additional pharmacologic means to inhibit the development and progression of diabetic retinopathy.