Sato H, Miki T, Vallabhapurapu R P, Wang P, Liu G S, Cohen M V, Downey J M
Department of Physiology, University of South Alabama, Mobile 36688, USA.
Basic Res Cardiol. 1997 Oct;92(5):339-50. doi: 10.1007/BF00788946.
We investigated the effects of 5-(N-ethyl-N-isopropyl)amiloride (EIPA) on infarction in isolated rabbit hearts and cardiomyocytes. Thirty min of regional ischemia caused 29.6 +/- 2.8% of the risk zone to infarct in untreated Krebs buffer-perfused hearts. Treatment with EIPA (1 microM) for 20 min starting either 15 min before ischemia or 15 min after the onset of ischemia significantly reduced infarction to 5.4 +/- 2.0% and 7.0 +/- 1.0%, respectively (p < 0.01 versus untreated hearts). In both cases salvage was very similar to that seen with ischemic preconditioning (PC) (7.1 +/- 1.5% infarction). Unlike the case with ischemic preconditioning, however, protection from EIPA was not blocked by 50 microM polymyxin B, a PKC inhibitor, or 1 microM glibenclamide, a KATP channel blocker. Forty-five min of regional ischemia caused 51.0 +/- 2.9% infarction in untreated hearts. Ischemic preconditioning reduced infarction to 23.4 +/- 3.1% (p < 0.001 versus untreated hearts). In these hearts with longer periods of ischemia pretreatment with EIPA reduced infarction similarly to 28.8 +/- 2.1% (p < 0.01 versus untreated hearts). However, when EIPA was combined with ischemic PC, no further reduction in infarction was seen (23.8 +/- 3.5% infarction). To further elucidate the mechanism of EIPA's cardioprotective effect, this agent was also examined in isolated rabbit cardiomyocytes. Preconditioning caused a delay of about 30 min in the progressive increase in osmotic fragility that occurs during simulated ischemia. In contrast, EIPA had no effect on the time course of ischemia-induced osmotic fragility. Furthermore, EIPA treatment did not alter the salutary effect of ischemic preconditioning when the two were combined in this model. We conclude that Na+/H+ exchange inhibition limits myocardial infarction in the isolated rabbit heart by a mechanism which is quite different from that of ischemic preconditioning. Despite the apparently divergent mechanisms, EIPA's cardioprotective effect could not be added to that of ischemic or metabolic preconditioning in these models.
我们研究了5-(N-乙基-N-异丙基)氨氯吡脒（EIPA）对离体兔心脏和心肌细胞梗死的影响。在未处理的用Krebs缓冲液灌注的心脏中，30分钟的局部缺血导致风险区域的29.6±2.8%发生梗死。在缺血前15分钟或缺血开始后15分钟开始用EIPA（1微摩尔）处理20分钟，梗死率分别显著降低至5.4±2.0%和7.0±1.0%（与未处理的心脏相比，p<0.01）。在这两种情况下，挽救情况与缺血预处理（PC）所见非常相似（梗死率为7.1±1.5%）。然而，与缺血预处理不同的是，EIPA的保护作用未被50微摩尔的蛋白激酶C（PKC）抑制剂多粘菌素B或1微摩尔的ATP敏感性钾通道（KATP）阻滞剂格列本脲阻断。45分钟的局部缺血在未处理的心脏中导致51.0±2.9%的梗死。缺血预处理将梗死率降低至23.4±3.1%（与未处理的心脏相比，p<0.001）。在这些缺血时间较长的心脏中，用EIPA预处理可使梗死率同样降低至28.8±2.1%（与未处理的心脏相比，p<0.01）。然而，当EIPA与缺血预处理联合使用时，未观察到梗死率进一步降低（梗死率为23.8±3.5%）。为了进一步阐明EIPA心脏保护作用的机制，还在离体兔心肌细胞中对该药物进行了研究。预处理使模拟缺血期间发生的渗透脆性逐渐增加延迟约30分钟。相比之下，EIPA对缺血诱导的渗透脆性的时间进程没有影响。此外，在该模型中，当两者联合使用时，EIPA处理并未改变缺血预处理的有益作用。我们得出结论，钠/氢交换抑制通过一种与缺血预处理截然不同的机制限制离体兔心脏的心肌梗死。尽管机制明显不同，但在这些模型中，EIPA的心脏保护作用不能叠加到缺血或代谢预处理的作用上。
