Khandoudi N, Laville M P, Bril A
SmithKline Beecham Laboratoires Pharmaceutiques, Saint-Grégoire, France.
J Cardiovasc Pharmacol. 1996 Oct;28(4):540-6. doi: 10.1097/00005344-199610000-00010.
We investigated the potential role of the Na+/H+ exchanger (NHE) during global low-flow ischemia. Isolated working rat hearts were subjected to a low-flow ischemic period of 30 or 60 min at 37 degrees C and then reperfused for 30 min. Under those conditions, the effects of two NHE inhibitors 3-methylsulphonyl-4-piperidinobenzoyl guanidine methanesulphonate (HOE-694, 1 microM) and 5-(N-ethyl-N-isopropyl) amiloride (EIPA, 1 microM), were compared. When added to the perfusion fluid 15 min before induction of ischemia, EIPA partially preserved aortic output (AO) during either a 30- or 60-min low-flow period. A lesser effect, which was not statistically significant, was observed with HOE-694. Therefore, after 30-min ischemia, AO was 18.7 +/- 2.7, 31.4 +/- 3.3% (p < 0.05 vs. control group) and 25.8 +/- 3.2% of the preischemic value in control and EIPA- and HOE-694-treated groups, respectively. Similarly, after 60-min low-flow ischemia, AO was 15.7 +/- 1.8, 32.7 +/- 4.2% (p < 0.05 vs. control group) and 23.3 +/- 5.6% in control and EIPA- and HOE-694-treated groups, respectively. When EIPA and HOE-694 were added to the perfusion solution during the 60-min ischemic period, i.e., at 15 min of low-flow ischemia, AO was maintained at 38.9 +/- 4.9 and 30.2 +/- 2.4% (vs. 15.7 +/- 1.8% in the controls) in HOE-694- and EIPA-treated groups, respectively. EIPA but not HOE-694 also significantly (p < 0.05) improved the AO recovery during reperfusion. When administered later during ischemia, EIPA but not HOE-694 caused some recovery of AO during the remainder of the ischemic period but did not aid recovery during reperfusion. Our data suggest that although inhibition of NHE may be of some benefit during low-flow ischemia, additional effects may be necessary to provide a more efficient cardioprotection. An additional action, e.g., inhibition of the Na+/HCO3- cotransporter, could explain the superior effect of EIPA with respect to HOE-694.
我们研究了钠氢交换体（NHE）在全心低流量缺血期间的潜在作用。将离体工作的大鼠心脏在37℃下进行30或60分钟的低流量缺血处理，然后再灌注30分钟。在这些条件下，比较了两种NHE抑制剂3 - 甲基磺酰基 - 4 - 哌啶苯甲酰胍甲磺酸盐（HOE - 694，1微摩尔）和5 - （N - 乙基 - N - 异丙基）阿米洛利（EIPA，1微摩尔）的作用。在缺血诱导前15分钟加入灌注液时，EIPA在30分钟或60分钟的低流量期间部分保留了主动脉输出量（AO）。HOE - 694的作用较小，且无统计学意义。因此，在30分钟缺血后，对照组、EIPA处理组和HOE - 694处理组的AO分别为缺血前值的18.7±2.7%、31.4±3.3%（与对照组相比，p<0.05）和25.8±3.2%。同样，在60分钟低流量缺血后，对照组、EIPA处理组和HOE - 694处理组的AO分别为缺血前值的15.7±1.8%、32.7±4.2%（与对照组相比，p<0.05）和23.3±5.6%。当在60分钟缺血期（即低流量缺血15分钟时）将EIPA和HOE - 694加入灌注溶液中时，HOE - 694处理组和EIPA处理组的AO分别维持在38.9±4.9%和30.2±2.4%（对照组为15.7±1.8%）。EIPA而非HOE - 694也显著（p<0.05）改善了再灌注期间的AO恢复。在缺血后期给予时，EIPA而非HOE - 694在缺血期剩余时间内使AO有所恢复，但对再灌注期间的恢复无帮助。我们的数据表明，虽然抑制NHE在低流量缺血期间可能有一定益处，但可能需要额外的作用来提供更有效的心脏保护。额外的作用，例如抑制钠/碳酸氢根共转运体，可以解释EIPA相对于HOE - 694的优越效果。
