Miyata Toshio, van Ypersele de Strihou Charles, Ueda Yasuhiko, Ichimori Kohji, Inagi Reiko, Onogi Hiroshi, Ishikawa Naoyoshi, Nangaku Masaomi, Kurokawa Kiyoshi
Institute of Medical Sciences and Department of Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
J Am Soc Nephrol. 2002 Oct;13(10):2478-87. doi: 10.1097/01.asn.0000032418.67267.f2.
The implication of advanced glycation end products (AGE) in the pathogenesis of atherosclerosis and of diabetic and uremic complications has stimulated a search for AGE inhibitors. This study evaluates the AGE inhibitory potential of several well-tolerated hypotensive drugs. Olmesartan, an angiotensin II type 1 receptor (AIIR) antagonist, as well as temocaprilat, an angiotensin-converting enzyme (ACE) inhibitor, unlike nifedipine, a calcium blocker, inhibit in vitro the formation of two AGE, pentosidine and N(epsilon)-carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose. This effect is shared by all tested AIIR antagonists and ACE inhibitors. On an equimolar basis, they are more efficient than aminoguanidine or pyridoxamine. Unlike the latter two compounds, they do not trap reactive carbonyl precursors for AGE, but impact on the production of reactive carbonyl precursors for AGE by chelating transition metals and inhibiting various oxidative steps, including carbon-centered and hydroxyl radicals, at both the pre- and post-Amadori steps. Their effect is paralleled by a lowered production of reactive carbonyl precursors. Finally, they do not bind pyridoxal, unlike aminoguanidine. Altogether, this study demonstrates for the first time that widely used hypotensive agents, AIIR antagonists and ACE inhibitors, significantly attenuate AGE production. This study provides a new framework for the assessment of families of AGE-lowering compounds according to their mechanisms of action.
晚期糖基化终末产物（AGE）在动脉粥样硬化、糖尿病及尿毒症并发症发病机制中的作用，激发了人们对AGE抑制剂的探索。本研究评估了几种耐受性良好的降压药物抑制AGE生成的潜力。与钙通道阻滞剂硝苯地平不同，血管紧张素II 1型受体（AIIR）拮抗剂奥美沙坦以及血管紧张素转换酶（ACE）抑制剂替莫卡普利，在非尿毒症糖尿病血浆、非糖尿病尿毒症血浆、糖尿病尿毒症血浆或用阿拉伯糖强化的牛血清白蛋白（BSA）孵育过程中，可在体外抑制两种AGE（戊糖苷和N-ε-羧甲基赖氨酸（CML））的形成。所有测试的AIIR拮抗剂和ACE抑制剂均有此作用。在等摩尔基础上，它们比氨基胍或吡哆胺更有效。与后两种化合物不同，它们不会捕获AGE的活性羰基前体，而是通过螯合过渡金属并抑制包括碳中心自由基和羟基自由基在内的各种氧化步骤，在阿马多里反应前和反应后阶段影响AGE活性羰基前体的产生。它们的作用伴随着活性羰基前体生成的减少。最后，与氨基胍不同，它们不结合吡哆醛。总之，本研究首次证明，广泛使用的降压药物AIIR拮抗剂和ACE抑制剂可显著减弱AGE的产生。本研究为根据其作用机制评估降低AGE的化合物家族提供了一个新框架。
