Ramasamy R, Schaefer S
Division of Cardiology, Department of Medicine College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
J Mol Cell Cardiol. 1999 Apr;31(4):785-97. doi: 10.1006/jmcc.1998.0908.
It has been previously suggested that alterations in sodium homeostasis, leading to calcium overload may play a part in the mediation of cardiac ischemic injury. It has been demonstrated that the Na+-H+ exchanger plays an important role with regard to the regulation of intracellular sodium during ischemia and reperfusion and that inhibition of the Na+-H+ exchanger during ischemia protects hearts from ischemic injury. Studies using chemically-induced diabetic animals have suggested that the cardiac Na+-H+ exchanger in the diabetic heart is impaired and is responsible for limiting the increase in sodium during ischemia. The extent to which the Na+-H+ exchanger contributes to increases in intracellular sodium during ischemia in diabetic hearts is unclear as direct measurements of exchanger activity have not been made in genetically diabetic hearts. Therefore, this paper aims to address the following issues: (a) is the Na+-H+ exchanger impaired in a genetically diabetic rat heart: (b) does this impairment result in lower [Na]i or [Ca]i during ischemia; and (c) does Na+-H+ exchanger inhibition limit injury and functional impairment in diabetic hearts during ischemia and reperfusion? These issues were examined by inhibiting the Na+-H+ exchanger with ethylisopropylamiloride (EIPA) in isolated perfused hearts from both genetically diabetic (BB/W) and non-diabetic rats. Levels of intracellular sodium, intracellular calcium, intracellular pH and high energy phosphates (using 23Na,19F, 31P NMR spectroscopies, respectively) during global ischemia and reperfusion were also measured. The impact of diabetes on Na+-H+ exchanger activity was assessed by measuring pH recovery of these hearts after an acid load. Creatine kinase release during reperfusion was used as a measure of ischemic injury. This study demonstrated that the Na+-H+ exchanger is impaired in diabetic hearts. Despite this impaired activity, inhibition of Na+-H+ exchanger protected diabetic hearts from ischemic injury and was associated with attenuation of the rise in sodium and calcium, and limitation of acidosis and preservation of ATP during ischemia. The data presented here favor the use of Na+-H+ exchanger inhibitors to protect ischemic myocardium in diabetics. Also, the data provides possible mechanisms for the altered susceptibility of diabetic hearts to ischemic injury.
先前有人提出，钠稳态的改变导致钙超载，可能在心脏缺血性损伤的介导过程中起作用。已经证明，钠-氢交换体在缺血和再灌注期间对细胞内钠的调节中起重要作用，并且在缺血期间抑制钠-氢交换体可保护心脏免受缺血性损伤。使用化学诱导的糖尿病动物的研究表明，糖尿病心脏中的心脏钠-氢交换体受损，并且是限制缺血期间钠增加的原因。由于尚未在遗传性糖尿病心脏中直接测量交换体活性，因此钠-氢交换体在糖尿病心脏缺血期间对细胞内钠增加的贡献程度尚不清楚。因此，本文旨在解决以下问题：（a）遗传性糖尿病大鼠心脏中的钠-氢交换体是否受损；（b）这种损伤是否导致缺血期间细胞内钠或钙降低；以及（c）抑制钠-氢交换体是否能限制糖尿病心脏在缺血和再灌注期间的损伤和功能障碍？通过用乙基异丙基氨氯吡咪（EIPA）抑制遗传性糖尿病（BB/W）和非糖尿病大鼠的离体灌注心脏中的钠-氢交换体来研究这些问题。还测量了全心缺血和再灌注期间细胞内钠、细胞内钙、细胞内pH和高能磷酸盐（分别使用23Na、19F、31P核磁共振波谱）的水平。通过测量这些心脏在酸负荷后的pH恢复来评估糖尿病对钠-氢交换体活性的影响。再灌注期间肌酸激酶的释放用作缺血性损伤的指标。这项研究表明，糖尿病心脏中的钠-氢交换体受损。尽管活性受损，但抑制钠-氢交换体可保护糖尿病心脏免受缺血性损伤，并与缺血期间钠和钙升高的减弱、酸中毒的限制以及ATP的保存有关。此处提供的数据支持使用钠-氢交换体抑制剂来保护糖尿病患者的缺血心肌。此外，这些数据为糖尿病心脏对缺血性损伤易感性改变提供了可能的机制。
