Yang Hung-Yu, Kao Pai-Feng, Chen Tso-Hsiao, Tomlinson Brian, Ko Wen-Chin, Chan Paul
Division of Cardiology, Taipei Medical University-Wan Fang Hospital, No. 111 Hsing-Lung Road, Sec. 3, Wen-Shan District, Taipei City 116, Taiwan.
J Clin Pharmacol. 2007 Mar;47(3):397-403. doi: 10.1177/0091270006296762.
The role of oxidative stress in the pathogenesis of vascular diseases such as hypertension has been well recognized. Angiotensin (Ang) II is regarded as a pro-oxidant because it can stimulate the production of reactive oxygen species. The purpose of this study was to evaluate whether treatment with the Ang II type 1 (AT(1)) receptor antagonist valsartan has an antioxidant effect in patients with mild to moderate hypertension. A randomized, double-blind, placebo-controlled study was conducted in 48 stage I and II hypertensive subjects. Patients were followed every 4 weeks for 12 weeks after randomization to valsartan titrated to 80 to 160 mg once or twice daily or matching placebo. The erythrocyte superoxide dismutase (SOD) activity and expression of SOD-mRNA in polymorphonuclear leukocytes were measured before and after treatment. Valsartan showed concentration-dependent inhibition of reactive oxygen species generation in polymorphonuclear leukocytes from hypertensive patients. The erythrocyte superoxide dismutase activity before treatment was more than 2 times higher in hypertensive subjects compared to normal controls. Superoxide dismutase activity decreased significantly after 12 weeks of treatment with valsartan but did not change with placebo. The amount of SOD-mRNA in the polymorphonuclear leukocytes decreased progressively over 3 months in the hypertensive subjects receiving valsartan treatment but did not change in the placebo group. The production of reactive oxygen species is increased in hypertension, and superoxide dismutase activity is increased, presumably as a compensatory mechanism. Treatment with valsartan but not placebo resulted in a progressive down-regulation of SOD-mRNA expression and a reduction in superoxide dismutase activity, suggesting antioxidant activity and a reduction of reactive oxygen species generation. These findings imply that AT(1) receptor antagonists may provide benefits to hypertensive patients beyond blood pressure reduction.
氧化应激在诸如高血压等血管疾病发病机制中的作用已得到充分认识。血管紧张素（Ang）II被视为一种促氧化剂，因为它能刺激活性氧的产生。本研究的目的是评估用1型血管紧张素II（AT(1)）受体拮抗剂缬沙坦治疗对轻至中度高血压患者是否具有抗氧化作用。对48例I期和II期高血压受试者进行了一项随机、双盲、安慰剂对照研究。随机分组后，患者接受缬沙坦治疗，剂量滴定至80至160mg，每日一次或两次，或匹配的安慰剂，每4周随访一次，共12周。在治疗前后测量红细胞超氧化物歧化酶（SOD）活性以及多形核白细胞中SOD-mRNA的表达。缬沙坦对高血压患者多形核白细胞中活性氧的产生表现出浓度依赖性抑制作用。与正常对照组相比，高血压受试者治疗前的红细胞超氧化物歧化酶活性高出2倍多。用缬沙坦治疗12周后，超氧化物歧化酶活性显著降低，但安慰剂治疗组无变化。接受缬沙坦治疗的高血压受试者多形核白细胞中SOD-mRNA的量在3个月内逐渐减少，但安慰剂组无变化。高血压患者体内活性氧的产生增加，超氧化物歧化酶活性增加，推测这是一种代偿机制。用缬沙坦而非安慰剂治疗导致SOD-mRNA表达逐渐下调以及超氧化物歧化酶活性降低，表明其具有抗氧化活性并减少了活性氧的产生。这些发现意味着AT(1)受体拮抗剂可能为高血压患者带来除降低血压之外的益处。
