Department of Physiology & Pharmacology, University of Western Ontario, Medical Sciences Building, London, Ontario, Canada N6A 5C1.
J Mol Cell Cardiol. 2013 Aug;61:77-82. doi: 10.1016/j.yjmcc.2013.02.006. Epub 2013 Feb 18.
The concept of NaH exchange (NHE) involvement in cardiac pathology has been espoused for decades and supported by a plethora of experimental studies demonstrating salutary effects of NHE inhibition in protecting the myocardium against ischemic and reperfusion injury as well as attenuating myocardial remodelling and heart failure. NHE is actually a family of sodium and proton transporting proteins of which 10 isoforms have been identified. Myocardial NHE is represented primarily by the ubiquitous NHE-1 subtype which is expressed in most tissues. The robust positive results seen with NHE-1 inhibitors in experimental studies have led to relatively rapid development of these pharmacological agents for clinical assessment especially as potential cardioprotective therapies. Yet clinical studies have revealed, at best, inconsistent results as evidenced by poor efficacy and serious side effects, the latter revealed with the use of the NHE-1 inhibitor cariporide in high-risk patients undergoing coronary artery bypass grafting and evidenced by an increased incidence of cerebrovascular events of thromboembolic origin. The lack of success in clinical trials coupled with potential for toxicity has had a negative impact on development of cardiac therapeutic agents which have been developed based on the concept of NHE-1 inhibition. Whether this response is justified is open for discussion although a close scrutiny of clinical trial outcomes suggests that it may not be and that NHE-1 inhibition, if applied appropriately continues to represent an effective, if not the most effective approach for myocardial salvage following ischemic insult. Moreover, in addition to its cardioprotective effects, emerging evidence further suggests that NHE-1 inhibition is an effective strategy to minimize myocardial remodelling as well as a potentially effective strategy to improve efficacy of resuscitation following cardiac arrest. Thus, NHE-1 inhibition continues to represent a potentially highly effective therapeutic approach for the treatment of heart disease. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".
钠氢交换（NHE）参与心脏病理的概念已经被提出了几十年，并得到了大量实验研究的支持，这些研究表明 NHE 抑制在保护心肌免受缺血再灌注损伤以及减轻心肌重构和心力衰竭方面具有有益的作用。NHE 实际上是一个钠和质子转运蛋白家族，其中已经鉴定出 10 种同工型。心肌 NHE 主要由普遍存在的 NHE-1 亚型代表，该亚型在大多数组织中表达。在实验研究中，NHE-1 抑制剂的强大阳性结果导致这些药理学制剂的临床评估相对迅速发展，特别是作为潜在的心脏保护治疗方法。然而，临床研究显示，最好的情况是，疗效不佳和严重副作用的证据不一致，这在后一种情况下使用 NHE-1 抑制剂 cariporide 在接受冠状动脉旁路移植术的高风险患者中得到了揭示，并通过血栓栓塞来源的脑血管事件发生率增加得到了证实。在临床试验中缺乏成功，加上潜在的毒性，对基于 NHE-1 抑制概念开发的心脏治疗药物的开发产生了负面影响。这种反应是否合理是可以讨论的，尽管对临床试验结果的仔细审查表明，情况可能并非如此，并且如果适当应用，NHE-1 抑制仍然代表缺血性损伤后心肌挽救的有效方法，即使不是最有效的方法。此外，除了其心脏保护作用外，新出现的证据还进一步表明，NHE-1 抑制是一种有效的策略，可以最大限度地减少心肌重构，并且是改善心脏骤停后复苏效果的潜在有效策略。因此，NHE-1 抑制仍然是治疗心脏病的一种潜在的高效治疗方法。本文是一个题为“心脏肌细胞中的钠调节”的特刊的一部分。
