Rohmann S, Weygandt H, Minck K O
Department of Preclinical Cardiovascular Research, E. Merck, Darmstadt, Germany.
Cardiovasc Res. 1995 Dec;30(6):945-51.
During reperfusion of ischaemic myocardium, Na+/H+ exchange promotes recovery from acidosis resulting in an accumulation of intracellular Na+. This leads to calcium overload via Na+/Ca2+ exchange and might result in cell necrosis contributing to reperfusion injury.
We assessed whether HOE 694, a specific inhibitor of Na+/H+ exchange, is able to reduce infarct size in swine myocardium. Experiments were performed in pentobarbitone-anaesthetized, open-chest pigs which were subjected to a 60 min occlusion of the left anterior descending coronary artery (LADCA) followed by 2 h of reperfusion. Three groups of animals were studied. In the pre-reperfusion group (pre-REP, n = 7) HOE 694 infusion (7 mg/kg/15 min) was started at 45 min of occlusion of the LADCA and continued until the end of occlusion, while in pre-occlusion group (pre-TCO, n = 7) HOE 694 infusion was started 15 min before occlusion and stopped at the onset of ischaemia. In the control group (n = 7) animals received vehicle alone. At the end of the protocol, infarct size (as d% of the left ventricular risk region) was determined by the p-nitroblue tetrazolium method. Treatment with HOE 694 prior to the ischaemic insult or upon reperfusion significantly reduced infarct size [4.1%(1.4%), P < 0.01 and 38.2%(5.8%), P < 0.05, respectively], compared with 77.7%(4.0%) in the control group. However, infarct size was significantly more reduced in the pre-TCO group than in the pre-REP group (P < 0.05).
Treatment with HOE 694 leads to a significant reduction in infarct size, even when administered after the onset of ischaemia. Thus, inhibition of Na+/H+ exchange was able to limit cell necrosis. This implicates an important role for Na+/H+ exchange in the pathogenesis of infarct expansion and provides evidence that reperfusion injury exists. However, HOE 694 was even more effective when given before ischaemia, indicating an additional protective effect during ischaemia which might be due to slowing down of a vicious cycle that consumes ATP and generates H+.
在缺血心肌再灌注期间，钠氢交换促进酸中毒的恢复，导致细胞内钠蓄积。这通过钠钙交换导致钙超载，并可能导致细胞坏死，从而造成再灌注损伤。
我们评估了钠氢交换特异性抑制剂HOE 694是否能够减小猪心肌梗死面积。实验在戊巴比妥麻醉、开胸的猪身上进行，这些猪左前降支冠状动脉（LADCA）闭塞60分钟，随后再灌注2小时。研究了三组动物。在再灌注前组（pre-REP，n = 7），在LADCA闭塞45分钟时开始输注HOE 694（7 mg/kg/15分钟），并持续至闭塞结束，而在闭塞前组（pre-TCO，n = 7），在闭塞前15分钟开始输注HOE 694，并在缺血开始时停止。在对照组（n = 7），动物仅接受赋形剂。在实验方案结束时，通过对硝基蓝四氮唑法测定梗死面积（以左心室危险区域的百分比表示）。与对照组的77.7%（4.0%）相比，在缺血损伤前或再灌注时用HOE 694治疗显著减小了梗死面积[分别为4.1%（1.4%），P < 0.01和38.2%（5.8%），P < 0.05]。然而，pre-TCO组的梗死面积减小幅度显著大于pre-REP组（P < 0.05）。
用HOE 694治疗可显著减小梗死面积，即使在缺血发作后给药也是如此。因此，抑制钠氢交换能够限制细胞坏死。这表明钠氢交换在梗死扩展的发病机制中起重要作用，并提供了再灌注损伤存在的证据。然而，HOE 694在缺血前给药时效果更佳，表明在缺血期间有额外的保护作用，这可能是由于减缓了消耗ATP并产生H⁺的恶性循环。
