Division of Experimental Cardiology, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Belgium.
Pharmacol Ther. 2012 Apr;134(1):26-42. doi: 10.1016/j.pharmthera.2011.12.001. Epub 2011 Dec 14.
The search for alternative anti-arrhythmic strategies is fueled by an unmet medical need as well as by the opportunities arising from identification of novel targets and novel drugs. Na/Ca exchange is a potential target involved in several types of arrhythmias, such as those related to ischemia-reperfusion, heart failure and also some forms of genetic arrhythmias. Inhibition of Na/Ca exchange is theoretically not only anti-arrhythmic but also increases cellular Ca(2+) content. This could be an advantage in conditions of low inotropy, such as in heart failure, but may also worsen conditions such as the recovery from ischemia or relaxation abnormalities. With the available drugs such as KB-R7943 and SEA-0400 these theories have now been tested in a number of cellular and in vivo models. Experience is overall rather positive and seems less hampered by the potential drawbacks than expected. This may be because the currently available drugs are not highly selective, with additional benefit derived from concurrent effects. While this precludes a definite answer regarding the benefit of a pure NCX inhibitor, they indicate that Na/Ca exchange inhibition as part of a multi-target strategy is an avenue to be considered. Such studies will need further 'bench' work and testing in relevant preclinical models, including chronic disease.
寻找替代抗心律失常策略的动力来自未满足的医疗需求，以及识别新靶点和新药带来的机会。钠钙交换是涉及多种类型心律失常的潜在靶点，如与缺血再灌注、心力衰竭相关的心律失常，以及某些形式的遗传性心律失常。理论上，抑制钠钙交换不仅具有抗心律失常作用，还能增加细胞内 Ca(2+)含量。在心肌收缩力降低的情况下，如心力衰竭，这可能是一个优势，但也可能使缺血恢复或舒张异常等情况恶化。目前已有 KB-R7943 和 SEA-0400 等药物在多种细胞和体内模型中进行了这些理论的验证。总体经验较为积极，似乎比预期的阻碍要小。这可能是因为目前可用的药物并非高度选择性，同时具有协同作用带来的额外益处。虽然这不能确定纯 NCX 抑制剂的益处，但它们表明，作为多靶点策略的一部分，抑制钠钙交换是值得考虑的途径。这些研究将需要进一步在相关临床前模型中进行“基础”工作和测试，包括慢性疾病。
