Böger Rainer H, Schwedhelm Edzard, Maas Renke, Quispe-Bravo Sabine, Skamira Cord
Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Germany.
Vasc Med. 2005 Jul;10 Suppl 1:S97-102. doi: 10.1191/1358863x05vm608oa.
The renin angiotensin system has been shown to be involved in the pathogenesis of vascular and renal sequelae of diabetes mellitus. In type 2 diabetes mellitus, angiotensin receptor blockers have been shown to exert clinical benefit by reducing the progression of diabetic nephropathy. They also improve endothelium-mediated vascular function. The latter effect is partly due to the reduction of angiotensin II-associated oxidative stress. Moreover, small clinical studies have shown that treatment with angiotensin receptor blockers also reduces the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. In the VIVALDI trial, the ability of the angiotensin receptor blocker telmisartan to reduce the progression of diabetic nephropathy (associated with proteinuria) in comparison with valsartan in more than 800 patients with type 2 diabetes during 1 year of treatment is being studied. In order to gain more detailed insight into the potential pathomechanisms associated with this effect, further end-points have been defined. Among these are the circulating levels of ADMA and the urinary excretion rate of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). The former is an endogenous inhibitor of NO-mediated vascular function(s) and a prospectively determined marker of major cardiovascular events and mortality; the latter is a lipid peroxidation product resulting from the nonenzymatic peroxidation of arachidonic acid, which exerts detrimental vascular effects similar to those of thromboxane A2. Urinary 8-iso-PGF2alpha has been shown in clinical studies to be an independent marker of cardiovascular disease. Highlighting the effects of telmisartan on ADMA and 8-iso-PGF levels in such a large cohort of diabetic patients will enhance our understanding of the roles of dysfunctional NO metabolism and redox mechanisms in the pathogenesis of end-organ damage and its prevention by pharmacotherapy with angiotensin receptor blockers.
肾素血管紧张素系统已被证明参与糖尿病血管和肾脏并发症的发病机制。在2型糖尿病中，血管紧张素受体阻滞剂已被证明可通过减缓糖尿病肾病的进展发挥临床益处。它们还能改善内皮介导的血管功能。后一种作用部分归因于血管紧张素II相关氧化应激的减轻。此外，小型临床研究表明，血管紧张素受体阻滞剂治疗还可降低不对称二甲基精氨酸（ADMA）的循环水平，ADMA是一氧化氮（NO）合酶的内源性抑制剂。在VIVALDI试验中，正在研究血管紧张素受体阻滞剂替米沙坦与缬沙坦相比，在1年治疗期间对800多名2型糖尿病患者减少糖尿病肾病（与蛋白尿相关）进展的能力。为了更深入地了解与这种作用相关的潜在发病机制，已确定了进一步的终点指标。其中包括ADMA的循环水平和8-异前列腺素F2α（8-iso-PGF2α）的尿排泄率。前者是NO介导的血管功能的内源性抑制剂，是主要心血管事件和死亡率的前瞻性确定标志物；后者是花生四烯酸非酶促过氧化产生的脂质过氧化产物，其对血管产生的有害作用类似于血栓素A2。临床研究表明，尿8-iso-PGF2α是心血管疾病的独立标志物。在如此大量的糖尿病患者队列中突出替米沙坦对ADMA和8-iso-PG水平的影响，将增进我们对功能失调的NO代谢和氧化还原机制在终末器官损伤发病机制中的作用以及通过血管紧张素受体阻滞剂药物治疗进行预防的理解。
