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, Mitsukaido, Japan.

出版信息

Circulation. 1997 Oct 21;96(8):2545-50. doi: 10.1161/01.cir.96.8.2545.

DOI:10.1161/01.cir.96.8.2545

PMID:9355892

Abstract

BACKGROUND

The attenuation of intracellular production of cGMP has been known to be a mechanism of nitrate tolerance. A recent in vitro study showed 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.

METHODS AND RESULTS

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 TID vitamin E group) or placebo (placebo group). Vasodilator response to nitroglycerin was assessed with forearm plethysmography by measurement of the change in the forearm blood flow before and 5 minutes 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 vitamin E or placebo alone was taken (day 3), and 3 days after application of a 10-mg/24-h nitroglycerin tape concomitantly with oral vitamin E or placebo (day 6). The responses of forearm blood flow (%FBF) and cGMP (%cGMP) after sublingual nitroglycerin on day 0 (%FBF: normal volunteers, 32+/-12 versus 31+/-11; IHD patients, 35+/-15 versus 34+/-15; %cGMP: normal volunteers, 38+/-10 versus 35+/-11; IHD patients, 37+/-11 versus 38+/-12, vitamin E group versus placebo group) and day 3 (%FBF: normal volunteers, 33+/-9 versus 32+/-12; IHD patients, 35+/-12 versus 33+/-13; %cGMP: normal volunteers, 38+/-10 versus 37+/-11; IHD patients, 36+/-14 versus 37+/-10, vitamin E group versus 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 versus 17+/-9, P<.01; IHD patients, 28+/-14 versus 17+/-8, P<.01; %cGMP: normal volunteers, 35+/-11 versus 8+/-5, P<.01; IHD patients, 38+/-10 versus 12+/-4, P<.01, vitamin E group versus placebo group).

CONCLUSIONS

These results indicate that the combination therapy with vitamin E is potentially a useful method to prevent the development of nitrate tolerance.

摘要

背景

细胞内环磷酸鸟苷（cGMP）生成的减弱是已知的硝酸酯耐受性的一种机制。最近一项体外研究显示，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弱。我们研究了抗氧化剂维生素E对硝酸酯耐受性发展的预防作用。

方法与结果

在这项双盲、安慰剂对照研究中，24名正常志愿者和24例缺血性心脏病患者（IHD患者）被随机分为接受维生素E组（维生素E组，200mg，每日三次）或安慰剂组（安慰剂组）。通过前臂体积描记法，在舌下含服0.3mg硝酸甘油前及含服后5分钟测量前臂血流变化，以此评估对硝酸甘油的血管舒张反应，同时从静脉取血样测量血小板cGMP水平。在前臂血流测量和血样采集在基线（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10mg/24小时硝酸甘油贴剂3天后（第6天）连续进行。第0天（%前臂血流：正常志愿者，32±12对31±11；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组对安慰剂组）和第3天（%前臂血流：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组对安慰剂组）舌下含服硝酸甘油后前臂血流（％FBF）和cGMP（％cGMP）的反应在两组间无差异。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<0.01，维生素E组对安慰剂组）。