Karmazyn M
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Ann N Y Acad Sci. 1999 Jun 30;874:326-34. doi: 10.1111/j.1749-6632.1999.tb09248.x.
There is convincing evidence that the Na-H exchanger (NHE) plays a pivotal role in mediating tissue injury during ischemia and reperfusion. Extensive studies with NHE inhibitors have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and animal species, particularly in terms of attenuating contractile dysfunction. These protective effects of NHE inhibition appear to be superior to other strategies, including ischemic preconditioning. Such studies have contributed greatly to the overwhelming evidence that NHE activation mediates ischemic and reperfusion injury. The NHE inhibitor HOE 642 (cariporide) is currently undergoing clinical evaluation in high-risk cardiac patients. Moreover, there is now emerging evidence that NHE may be involved in mediating cardiotoxicity directly produced by various ischemic metabolites such as lipid amphiphiles or reactive oxygen species. NHE inhibition also attenuates apoptosis in the ischemic myocardium, a process that may be of importance in the subsequent development of postinfarction heart failure. In conclusion, NHE represents an important adaptive process in response to intracellular acidosis that results in a paradoxical contribution to cardiac tissue injury.
有确凿证据表明，钠氢交换体（NHE）在介导缺血再灌注期间的组织损伤中起关键作用。使用NHE抑制剂进行的大量研究一致表明，在多种实验模型和动物物种中，其对缺血再灌注损伤具有保护作用，尤其是在减轻收缩功能障碍方面。NHE抑制的这些保护作用似乎优于其他策略，包括缺血预处理。此类研究极大地推动了以下压倒性证据的形成：NHE激活介导缺血再灌注损伤。NHE抑制剂HOE 642（卡立泊来德）目前正在高危心脏病患者中进行临床评估。此外，现在有新证据表明，NHE可能参与介导由各种缺血代谢产物（如脂质两亲物或活性氧）直接产生的心脏毒性。NHE抑制还可减轻缺血心肌中的细胞凋亡，这一过程可能在心肌梗死后心力衰竭的后续发展中具有重要意义。总之，NHE代表了对细胞内酸中毒的一种重要适应性过程，而这一过程却对心脏组织损伤产生了矛盾的影响。
