Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy.
Clin Res Cardiol. 2012 Jun;101(6):453-9. doi: 10.1007/s00392-012-0412-x.
Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure.
In a randomized, investigator-blind parallel trial, 30 healthy (age 25-32) volunteers were randomized to receive (1) transdermal GTN (0.6 mg/h) administered for 2 h a day for 6 days; (2) oral PETN (80 mg) once a day for 6 days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8 ± 2.1%; after IR 1.0 ± 2.1%; P < 0.01). Daily, 2-h exposure to GTN partially prevented IR-induced endothelial dysfunction (FMD before IR: 7.7 ± 2.4%; after IR 4.3 ± 3.0%; P < 0.01 compared to before IR). In contrast, daily PETN administration afforded greater protection from IR-induced endothelial injury (FMD before IR: 7.9 ± 1.7%; after IR 6.4 ± 5.3%, P = ns; P < 0.05 ANOVA across groups). In vitro, incubation of human endothelial cells with GTN (but not PETN) was associated with inhibition (P < 0.01) of aldehyde dehydrogenase, an enzyme that is important for both nitrate biotransformation and ischemic preconditioning.
We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.
缺血和药物预处理具有很大的临床潜力，但在重复暴露过程中，其效果是否能持续还不清楚。我们之前已经证明，硝酸甘油（GTN）的急性保护作用在每天重复给药时会减弱。戊四硝酯（PETN）是一种具有不同血流动力学和生化特性的有机硝酸盐。本实验的目的是研究 PETN 和 GTN 在重复每日暴露期间的预处理样作用。
在一项随机、研究者盲法的平行试验中，将 30 名健康（年龄 25-32 岁）志愿者随机分为三组：（1）每天接受 2 小时的透皮 GTN（0.6mg/h）治疗，连续 6 天；（2）每天口服 PETN（80mg），连续 6 天；（3）不接受治疗。一周后，在缺血再灌注（IR）前后评估内皮依赖性血流介导的扩张。IR 导致对照组内皮依赖性松弛明显减弱（IR 前 FMD：5.8±2.1%；IR 后 1.0±2.1%；P<0.01）。每天 2 小时暴露于 GTN 可部分预防 IR 诱导的内皮功能障碍（IR 前 FMD：7.7±2.4%；IR 后 4.3±3.0%；与 IR 前相比，P<0.01）。相比之下，每天给予 PETN 可提供更大的保护作用，防止 IR 诱导的内皮损伤（IR 前 FMD：7.9±1.7%；IR 后 6.4±5.3%，P=ns；P<0.05 组间 ANOVA）。在体外，用 GTN（但不用 PETN）孵育人内皮细胞与醛脱氢酶（ALDH）抑制相关（P<0.01），ALDH 是硝酸盐生物转化和缺血预处理的重要酶。
我们之前已经表明，在重复给药后，GTN 的预处理样作用会减弱。本研究数据表明，两种硝酸盐的保护程度存在梯度，提示在缺血诱导的内皮功能障碍的人体体内模型中，PETN 诱导的预处理在延长给药后仍能持续。使用分离的人内皮细胞，我们根据 GTN 与 PETN 对线粒体醛脱氢酶活性的不同影响，提出了这一观察结果的机制解释。
