Optimal dose and mode of delivery of Na+/H+ exchange-1 inhibitor are critical for reducing postsurgical ischemia-reperfusion injury
Optimal dose and mode of delivery of Na+/H+ exchange-1 inhibitor are critical for reducing postsurgical ischemia-reperfusion injury
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DOI：
10.1016/s0003-4975(03)00958-5
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发表时间：
2003-11-01
影响因子：
4.6
通讯作者：
Vinten-Johansen, J
中科院分区：
文献类型：
--
作者：
Corvera, JS;Zhao, ZQ;Vinten-Johansen, J
背景。在临床试验中，围手术期静脉注射Na+/H+交换异构体-1 （NHE1）抑制剂对手术再灌注的高危患者仅具有中等疗效（GUARDIAN试验）。然而，NHE1抑制剂的有效心肌浓度可能无法通过单独的肠外给药来实现。我们验证了增加NHE1抑制剂EMD 87580（（2-甲基-4,5-二-（甲基磺酰基）-苯甲酰）-胍）在心脏骤停（BCP）血液再灌注和肠外再灌注时给药剂量可减少进展性梗死手术再灌注后心肌损伤的假设。26只被麻醉的狗接受了75分钟的左冠状动脉前降支闭塞术，随后进行了体外循环和60分钟的多剂量10度BCP停搏。对照组（n = 8）不补充BCP。在三个EMD-BCP组中，在BCP中添加10 μ mol/L EMD 87580 （EMD-10, n = 5）、20 μ mol/L EMD 87580 （EMD-20, n = 5）或20 μ mol/L EMD 87580联合立即再灌注丸（静脉注射5 mg/kg） （EMD- 20r, n = 8）。在第二次BCP输注前释放左冠状动脉前降支闭塞。停止体外循环后再灌注持续120分钟。在所有组中，危险区域的缺血后收缩和舒张功能都是不正常的。与对照组（30.7% +/- 2.4%）相比，EMD-10组（26.2% +/- 3.6%）和EMD-20组（22.5% +/- 2.4%）的梗死面积（危险面积百分比）没有显著减少；然而，EMD-20R组梗死面积明显减小（16.1% +/- 2.8%,p = 0.003）。EMD-10组（81.1% +/- 0.5%含水量）、EMD-20组（81.7% +/- 0.3%）和EMD-20R组（81.9% +/- 0.3%）危险部位水肿均小于对照组（83.2% +/- 0.2%），差异有统计学意义（p < 0.056）。与对照组相比，EMD-20R组缺血后高危区心肌的中性粒细胞积累（髓过氧化物酶活性）更少（5.3 +/- 0.7比8.7 +/- 1.4吸收单位）。分钟(1)。g (1);p = 0.05)，提示缺血后炎症反应减弱。经停搏联合肠外给药NHE1抑制剂可显著减轻局部缺血手术再灌注后心肌损伤。NHE1抑制剂的递送时间、剂量和方式对其疗效至关重要。(C) 2003年由胸外科学会出版。
Background. In clinical trials, perioperative intravenous Na+/H+ exchange isoform-1 (NHE1) inhibitors were only moderately effective in high-risk patients undergoing surgical reperfusion (GUARDIAN trial). However, effective myocardial concentrations of NHE1 inhibitor may not have been achieved by parenteral administration alone. We tested the hypothesis that increasing doses of NHE1 inhibitor EMD 87580 ((2-methyl-4,5-di-(methylsulfonyl)-benzoyl)-guanidine) delivered in blood cardioplegia (BCP) and by parenteral route at reperfusion reduce myocardial injury after surgical reperfusion of evolving infarction.Methods. Twenty-six anesthetized dogs underwent 75 minutes of left anterior descending coronary artery occlusion, followed by cardiopulmonary bypass and 60 minutes of arrest with multidose 10degreesC BCP. In the control group (n = 8), BCP was not supplemented. In the three EMD-BCP groups, BCP was supplemented with 10 mumol/L EMD 87580 (EMD-10, n = 5), 20 mumol/L EMD 87580 (EMD-20, n = 5), or 20 mumol/L EMD 87580 combined with an immediate reperfusion bolus (5 mg/kg intravenously) (EMD-20R, n = 8). The left anterior descending coronary artery occlusion was released just before the second infusion of BCP. Reperfusion continued for 120 minutes after discontinuation of cardiopulmonary bypass.Results. Postischemic systolic and diastolic function in the area at risk was dyskinetic in all groups. Infarct size (percentage of area at risk) was not significantly reduced in the EMD-10 (26.2% +/- 3.6%) and EMD-20 (22.5% +/- 2.4%) groups versus control (30.7% +/- 2.4%); however, infarct size was significantly reduced in the EMD-20R group (16.1% +/- 2.8%, p = 0.003). Edema in the area at risk in the EMD-10 (81.1% +/- 0.5% water content), EMD-20 (81.7% +/- 0.3%), and EMD-20R (81.9% +/- 0.3%) groups was less than in controls (83.2% +/- 0.2%), (p < 0.056). Neutrophil accumulation (myeloperoxidase activity) in postischemic area-at-risk myocardium was less in the EMD-20R group versus the control group (5.3 +/- 0.7 versus 8.7 +/- 1.4 absorbance units . min(-1) . g(-1); p = 0.05), which suggests an attenuated postischemic inflammatory response.Conclusions. Optimal delivery of NHE1 inhibitor to the heart through combined cardioplegia and parenteral routes significantly attenuates myocardial injury after surgical reperfusion of regional ischemia. Timing, dose, and mode of delivery of NHE1 inhibitors are important to their efficacy. (C) 2003 by The Society of Thoracic Surgeons.