Hoque A N, Karmazyn M
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Western Ontario, London, Canada.
Can J Physiol Pharmacol. 1997 Apr;75(4):326-34.
Sodium-hydrogen exchange (NHE) represents an important process mediating myocardial ischemic and reperfusion injury, and NHE inhibitors have been shown to be effective cardioprotective agents against this form of injury. The precise mechanisms by which NHE inhibition protect the heart are not known and we therefore postulated that attenuation of oxidative stress could contribute to such protection. Accordingly, we examined whether the potent and specific NHE inhibitor 4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate (HOE 642, 5 microM) can protect isolated rat hearts against mechanical and biochemical impairment produced by either hydrogen peroxide (150 or 200 microM) or a free radical generating system consisting of purine (4.6 or 9.2 mM) and xanthine oxidase (20 or 40 U/L). HOE 642 significantly delayed and attenuated both the depression in left ventricular developed pressure (LVDP) as well as the elevation in left ventricular end-diastolic pressure (LVEDP) produced by both concentrations of hydrogen peroxide, although greater protection was generally seen against the lower hydrogen peroxide concentration, particularly with respect to LVEDP. Hydrogen peroxide, at both concentrations, significantly reduced high energy phosphate and glycogen contents and elevated lactate levels, all of which were significantly attenuated by HOE 642. In contrast, HOE 642 had no effect on functional impairment produced by either concentration of the free radical generating system. At its lower concentration, the combination of purine plus xanthine oxidase had no effect on energy metabolites, although a significant reduction in high energy phosphate stores was seen with the higher concentration. However, this was unaffected by HOE 642. The protective effect of HOE 642 was mimicked by another NHE inhibitor, methylisobutylamiloride (MIA, 5 microM). Our study therefore shows that NHE inhibition selectively protects against functional and metabolic impairment produced by hydrogen peroxide. Since hydrogen peroxide formation has been implicated in the development of ischemic and reperfusion injury, it is possible that the protective effect of NHE inhibition against this form of oxidative stress may explain in part the basis for the well-established salutary actions of NHE inhibitors in the ischemic and reperfused myocardium. Since HOE 642 failed to modify the response to free radical generators, it is unlikely that the protective effects of NHE inhibitors can be explained by a free radical scavenging mechanism.
钠氢交换（NHE）是介导心肌缺血和再灌注损伤的一个重要过程，并且NHE抑制剂已被证明是针对这种损伤形式的有效心脏保护剂。NHE抑制发挥心脏保护作用的确切机制尚不清楚，因此我们推测氧化应激的减轻可能有助于这种保护作用。相应地，我们研究了强效特异性NHE抑制剂4-异丙基-3-甲基磺酰基苯甲酰胍甲磺酸盐（HOE 642，5微摩尔）是否能保护离体大鼠心脏免受过氧化氢（150或200微摩尔）或由嘌呤（4.6或9.2毫摩尔）和黄嘌呤氧化酶（20或40单位/升）组成的自由基生成系统所产生的机械和生化损伤。HOE 642显著延迟并减轻了两种浓度过氧化氢所引起的左心室舒张末压（LVDP）降低以及左心室舒张末压（LVEDP）升高，尽管通常对较低浓度的过氧化氢具有更大的保护作用，特别是在LVEDP方面。两种浓度的过氧化氢均显著降低了高能磷酸盐和糖原含量，并升高了乳酸水平，而HOE 642均使其显著减轻。相比之下，HOE 642对两种浓度的自由基生成系统所产生的功能损伤均无影响。在较低浓度下，嘌呤加黄嘌呤氧化酶的组合对能量代谢物无影响，尽管在较高浓度下观察到高能磷酸盐储备显著减少。然而，这不受HOE 642的影响。另一种NHE抑制剂甲基异丁基阿米洛利（MIA，5微摩尔）模拟了HOE 642的保护作用。因此，我们的研究表明NHE抑制选择性地保护心脏免受过氧化氢所产生的功能和代谢损伤。由于过氧化氢的形成与缺血和再灌注损伤的发生有关，NHE抑制对这种氧化应激形式的保护作用可能部分解释了NHE抑制剂在缺血和再灌注心肌中已确立的有益作用的基础。由于HOE 642未能改变对自由基生成剂的反应，NHE抑制剂的保护作用不太可能通过自由基清除机制来解释。
