长期服用单硝酸异山梨酯进行偏心训练后内皮功能得以保留，尽管存在中度硝酸酯耐受性。

Preserved endothelial function after long-term eccentric isosorbide mononitrate despite moderate nitrate tolerance.

作者信息

Müller Senta, Laber Ute, Müllenheim Jost, Meyer Wilfried, Kojda Georg

机构信息

Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Duesseldorf, Germany.

出版信息

J Am Coll Cardiol. 2003 Jun 4;41(11):1994-2000. doi: 10.1016/s0735-1097(03)00392-9.

DOI:10.1016/s0735-1097(03)00392-9

PMID:12798571

Abstract

OBJECTIVES

We sought to investigate the effects of orally administered, long-term, eccentric isosorbide mononitrate (ISMN) on endothelial function.

BACKGROUND

Previous studies have shown that nitrate tolerance induced by continuous transdermal glyceryl trinitrate (GTN) is associated with increased vascular superoxide production and endothelial dysfunction. In contrast, it is unclear whether vascular superoxide increases during eccentric administration of oral nitrates, which is a widely used therapeutic dosing regimen.

METHODS

New Zealand White rabbits were randomly classified into three groups (n = 10, each) that received either placebo, ISMN at 2 mg/kg body weight per day (ISMN-2), or ISMN at 200 mg/kg body weight per day (ISMN-200) in an eccentric, twice-daily scheme for four months. Animals were sacrificed 3 h after application of the last ISMN dose.

RESULTS

The continuously present, lowest ISMN plasma levels (ng/ml) were 4.8 +/- 0.2 in ISMN-2 and 14.5 +/- 4 in ISMN-200 (p = 0.026). Treatment with ISMN had no effect on aortic reactivity to phenylephrine, acetylcholine, or the nitric oxide (NO) donor S-nitroso-N-acetyl-D,L-penicillamine, while the half-maximal effective concentration of ISMN (EC(50)-value in -logM) was shifted from 5.23 +/- 0.03 (placebo) to 4.69 +/- 0.04 (ISMN-200) (p < 0.0001 by analysis of variance). This moderate in vivo nitrate tolerance was not associated with increased aortic superoxide production (5 micromol/l lucigenin). The cumulative (20-min) lucigenin signals (cpm/mg) were 211 +/- 34 (ISMN-200) and 230 +/- 22 (placebo) (p = 0.415).

CONCLUSIONS

Long-term treatment with high-dose, eccentric ISMN does not increase vascular superoxide production and/or impair endothelium-dependent vasorelaxation, despite the development of moderate nitrate tolerance. Thus, it is unlikely that long-term anti-ischemic treatment with ISMN aggravates endothelial dysfunction in coronary artery disease.

摘要

目的

我们试图研究口服长期偏心给药单硝酸异山梨酯（ISMN）对内皮功能的影响。

背景

先前的研究表明，持续经皮给予硝酸甘油（GTN）诱导的硝酸盐耐受性与血管超氧化物生成增加和内皮功能障碍有关。相比之下，尚不清楚在广泛使用的治疗给药方案——口服硝酸盐偏心给药期间血管超氧化物是否会增加。

方法

将新西兰白兔随机分为三组（每组n = 10），采用偏心、每日两次的给药方案，分别给予安慰剂、每天2 mg/kg体重的ISMN（ISMN - 2）或每天200 mg/kg体重的ISMN（ISMN - 200），持续四个月。在最后一次给予ISMN剂量3小时后处死动物。

结果

ISMN - 2组持续存在的最低血浆水平（ng/ml）为4.8±0.2，ISMN - 200组为14.5±4（p = 0.026）。ISMN治疗对主动脉对去氧肾上腺素、乙酰胆碱或一氧化氮（NO）供体S - 亚硝基 - N - 乙酰 - D，L - 青霉胺的反应性没有影响，而ISMN的半数最大有效浓度（EC(50)值，单位为 - logM）从5.23±0.03（安慰剂）变为4.69±0.04（ISMN - 200）（方差分析p < 0.0001）。这种中度的体内硝酸盐耐受性与主动脉超氧化物生成增加（5微摩尔/升光泽精）无关。累积（20分钟）光泽精信号（cpm/mg）在ISMN - 200组为211±34，安慰剂组为230±22（p = 0.415）。