[补充维生素E对减轻硝酸盐耐受性发展影响的随机、双盲、安慰剂对照研究]

[Randomized, double-blind, placebo-controlled study of supplemental vitamin E on attenuation of the development of nitrate tolerance].

作者信息

Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y

机构信息

Department of Cardiology, Kinu Medical Association Hospital, Ibaraki.

出版信息

J Cardiol. 1998 Mar;31(3):173-81.

PMID:9557281

Abstract

The attenuation of intracellular production of cyclic guanosine monophosphate (cGMP) has been known as a mechanism of nitrate tolerance. A recent in vitro study have shown an increase in superoxide levels and a reduced activation of guanylate cyclase in tolerant vessels. We investigated the preventive effect of an antioxidant, vitamin E, on the development of nitrate tolerance. In this double-blind, placebo-controlled study, 24 normal volunteers and 24 patients with ischemic heart disease (IHD patients) were randomized to receive either vitamin E (200 mg t. i. d.; vitamin E group) or placebo (placebo group). Vasodilator response to nitroglycerin was assessed with forearm plethysmography by measuring the change in the forearm blood flow before and 5 min after sublingual administration of 0.3 mg nitroglycerin, and at the same time, blood samples were taken from veins to measure the platelet cGMP level. Measurements of the forearm blood flow and blood sampling were obtained serially at baseline (day 0), 3 days after taking vitamin E or placebo alone (day 3), and 3 days after application of a 10 mg/24 hr nitroglycerin tape concomitantly with oral vitamin E or placebo (day 6). The response of forearm blood flow (%FBF) and cGMP (%cGMP) after sublingual nitroglycerin on day 0(%FBF: normal volunteers 32 +/- 12% vs 31 +/- 11%, IHD patients 35 +/- 15% vs 34 +/- 15%; %cGMP: normal volunteers 38 +/- 10% vs 35 +/- 11%, IHD patients 37 +/- 11% vs 38 +/- 12%; vitamin E group as placebo group) and day 3(%FBF: normal volunteers 33 +/- 9% vs 32 +/- 12%, IHD patients 35 +/- 12% vs 33 +/- 13%, %cGMP: normal volunteers 38 +/- 10% vs 37 +/- 11%, IHD patients 36 +/- 14% vs 37 +/- 10%, vitamin E group vs placebo group) were not different between the two groups. On day 6 %FBF and %cGMP in the placebo group were significantly lower compared with day 0, and there were significant differences in them between the two groups (%FBF: normal volunteers 30 +/- 12% vs 17 +/- 9%, p < 0.01; IHD patients 28 +/- 14% vs 17 +/- 8%, p < 0.01; %cGMP: normal volunteers 35 +/- 11% vs 8 +/- 5%, p < 0.01; IHD patients 38 +/- 10% vs 12 +/- 4%, p < 0.01, vitamin E group vs placebo group). In conclusion, the combination therapy with vitamin E is potentially a useful method to prevent the development of nitrate tolerance.

摘要

细胞内环磷酸鸟苷（cGMP）生成的减弱一直被认为是硝酸盐耐受性的一种机制。最近一项体外研究表明，在产生耐受性的血管中，超氧化物水平升高，鸟苷酸环化酶的激活减少。我们研究了抗氧化剂维生素E对硝酸盐耐受性发展的预防作用。在这项双盲、安慰剂对照研究中，24名正常志愿者和24名缺血性心脏病患者（IHD患者）被随机分为接受维生素E（200毫克，每日三次；维生素E组）或安慰剂（安慰剂组）。通过测量舌下含服0.3毫克硝酸甘油前后5分钟前臂血流量的变化，用前臂体积描记法评估对硝酸甘油的血管舒张反应，同时从静脉采集血样以测量血小板cGMP水平。在前臂血流量测量和血样采集分别在基线（第0天）、单独服用维生素E或安慰剂3天后（第3天）以及在口服维生素E或安慰剂的同时应用10毫克/24小时硝酸甘油贴剂3天后（第6天）连续进行。第0天舌下含服硝酸甘油后前臂血流量反应（%FBF）和cGMP反应（%cGMP）（%FBF：正常志愿者32±12%对31±l l%，IHD患者35±15%对34±15%；%cGMP：正常志愿者38±10%对35±11%，IHD患者37±11%对38±12%；维生素E组与安慰剂组）以及第3天（%FBF：正常志愿者33±9%对32±12%，IHD患者35±12%对33±13%，%cGMP：正常志愿者38±10%对37±11%，IHD患者36±14%对37±10%，维生素E组与安慰剂组）两组之间无差异。在第6天，安慰剂组的%FBF和%cGMP与第0天相比显著降低，且两组之间存在显著差异（%FBF：正常志愿者30±12%对17±9%，p<0.01；IHD患者28±14%对17±8%，p<0.01；%cGMP：正常志愿者35±11%对8±5%，p<0.01；IHD患者38±10%对12±4%，p<0.；维生素E组与安慰剂组）。总之，维生素E联合治疗可能是预防硝酸盐耐受性发展的一种有用方法。