Myers M L, Farhangkhoee P, Karmazyn M
Division of Cardiovascular Surgery, London Health Sciences Centre-Victoria, Ontario, Canada.
Cardiovasc Res. 1998 Nov;40(2):290-6. doi: 10.1016/s0008-6363(98)00183-7.
Sodium-hydrogen exchange (NHE) activation is a major mechanism of cardiac injury produced by ischemia and reperfusion. In addition, NHE may mediate the direct effects of hydrogen peroxide (H2O2) in normally perfused hearts. The present study was done to determine whether H2O2 at low concentrations producing mild myocardial depression affects post-ischemic recovery of function and to determine the ability of the NHE inhibitor HOE 642 to modulate this effect.
Isolated Langendorff-perfused rat hearts with a left ventricular balloon inflated to an initial end-diastolic pressure of 5 mmHg were subjected to 90 min of global zero-flow ischemia followed by 60 min reperfusion. In Study 1, hearts were randomized for perfusion with or without H2O2 (20 microM) for 15 min before ischemia and throughout reperfusion. In Study 2, identical experiments were done except that the hearts were pretreated with the NHE inhibitor HOE 642 (5 microM). Function was assessed by determining intraventricular pressures.
Recovery of developed pressure in Study 1 after 10 min reperfusion was 60.3 +/- 8% of pre-ischemic values in control hearts whereas this was reduced to 29.9 +/- 10% in hearts treated with H2O2 (P < 0.05). After 60 min of reperfusion recovery of developed pressure was 80.3 +/- 5.2% and 60.7 +/- 7% in control and H2O2-treated hearts, respectively (P < 0.05). Recovery of rates of pressure development (+dP/dt) and relaxation (-dP/dt) paralleled the effects seen with developed pressure. Moreover, these effects were associated with significantly elevated end-diastolic pressure during the last 20 min of reperfusion. In Study 2, HOE 642 completely prevented the deleterious effect of H2O2, both with respect to ventricular recovery and to the elevation in end-diastolic pressure during reperfusion.
Our results show that very low concentrations of H2O2 significantly impair recovery of function in this rat model of myocardial ischemia-reperfusion. Moreover, our results suggest that this effect is likely dependent on NHE activity and can be prevented by treatment with the NHE inhibitor HOE 642.
钠氢交换（NHE）激活是缺血再灌注所致心脏损伤的主要机制。此外，NHE可能介导过氧化氢（H2O2）在正常灌注心脏中的直接作用。本研究旨在确定低浓度H2O2导致轻度心肌抑制时是否会影响缺血后功能恢复，并确定NHE抑制剂HOE 642调节这种作用的能力。
将左心室球囊充气至初始舒张末期压力为5 mmHg的离体Langendorff灌注大鼠心脏进行90分钟全心零流量缺血，随后再灌注60分钟。在研究1中，心脏随机分为在缺血前及整个再灌注过程中灌注或不灌注H2O2（20 μM）15分钟。在研究2中，进行相同的实验，但心脏先用NHE抑制剂HOE 642（5 μM）预处理。通过测定心室内压力评估心脏功能。
在研究1中，再灌注10分钟后，对照心脏的左心室发展压恢复至缺血前值的60.3±8%，而用H2O2处理的心脏中该值降至29.9±10%（P<0.05）。再灌注60分钟后，对照心脏和用H2O2处理的心脏的左心室发展压恢复率分别为80.3±5.2%和60.7±7%（P<0.05）。压力上升速率（+dP/dt）和下降速率（-dP/dt）的恢复情况与左心室发展压的变化趋势一致。此外，这些效应与再灌注最后20分钟内心脏舒张末期压力显著升高有关。在研究2中，HOE 642完全预防了H2O2对心室功能恢复以及再灌注期间舒张末期压力升高的有害作用。
我们的结果表明，极低浓度的H2O2会显著损害该大鼠心肌缺血再灌注模型中的功能恢复。此外，我们的结果表明这种作用可能依赖于NHE活性，并且可以通过用NHE抑制剂HOE 642治疗来预防。
