ACE inhibitor and prevention of diabetic retinopathy

ACE抑制剂与糖尿病视网膜病变的预防

• 批准号: 6641268
• 负责人: JINZHONG ZHANG
• 金额: $ 15.3万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6641268
• 关键词: ACE inhibitors; affinity chromatography; angiotensin II; antihypertensive agents; atenolol; bradykinin; calcium channel blockers; captopril; chemoprevention; chlorothiazide; diabetes mellitus; diabetic retinopathy; disease /disorder prevention /control; drug screening /evaluation; glucose metabolism; hyperglycemia; ion exchange chromatography; laboratory rat; lisinopril; organ culture; polymerase chain reaction; scintillation counter; terminal nick end labeling; tissue /cell culture; western blottings

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.

描述（由申请人提供）：多项临床研究发现ACE（血管紧张素转换酶）抑制剂对糖尿病视网膜病变具有意想不到的抑制作用，但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机制的主要启动因素，我们研究了ACE抑制剂卡托普利对糖尿病大鼠视网膜血糖水平的影响。我们的初步数据表明，卡托普利可抑制糖尿病引起的糖尿病大鼠视网膜中葡萄糖的积累。同样，卡托普利显着抑制在升高的葡萄糖浓度下培养的视网膜细胞中的细胞内葡萄糖积累，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，细胞内可以产生山梨醇，在糖尿病患者的视网膜中，山梨醇同样增加，并被卡托普利抑制，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。这些发现表明，ACE抑制剂对糖尿病视网膜病变发展的有益作用可能部分是由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。拟议的项目将确定抑制糖尿病视网膜中葡萄糖积聚是否是一般抗高血压药物的特征，还是一类抗高血压药物或一种药物所独有的，并研究 ACE 抑制剂抑制细胞内葡萄糖代谢的机制。葡萄糖积累。 抑制葡萄糖积累代表了一种新的机制，表明 ACE 抑制剂对糖尿病视网膜病变的发展具有有益作用。我们相信具有这种作用的药物可以被表征和改进，从而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。