ACE inhibitor and prevention of diabetic retinopathy

描述（由申请人提供）：几项临床研究发现ACE（血管紧张素转换酶）抑制剂对糖尿病视网膜病变有意想不到的抑制作用，其作用机制尚不清楚。鉴于有证据表明高血糖的严重程度是视网膜病变发病的主要启动因素，我们研究了ACE抑制剂卡托普利对糖尿病大鼠视网膜葡萄糖水平的影响。我们的初步数据表明，卡托普利抑制糖尿病大鼠视网膜中葡萄糖的积累。同样，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积累，这表明视网膜组织中葡萄糖积累的抑制并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，可以在细胞内产生山梨醇，同样，糖尿病视网膜中山梨醇也会增加，而卡托普利会抑制山梨醇，进一步证明糖尿病大鼠视网膜细胞内葡萄糖升高，卡托普利抑制葡萄糖的积累。这些发现提示了一个总体假设，即ACE抑制剂对糖尿病视网膜病变发展的有益作用可能部分源于抑制视网膜细胞内葡萄糖积累，从而限制高血糖代谢后遗症的激活。拟议的项目将确定糖尿病视网膜中葡萄糖积累的抑制是一般降压药物的特征，还是一类降压药物所特有的，或者是一种药物，并研究ACE抑制剂抑制细胞内葡萄糖积累的机制。抑制葡萄糖积累是观察到的ACE抑制剂对糖尿病视网膜病变发展有益作用的新机制。我们相信，具有这种作用的药物可以被表征和改进，提供一种额外的药理学手段来抑制糖尿病视网膜病变的发生和进展。

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.