Shivkumar K, Deutsch N A, Lamp S T, Khuu K, Goldhaber J I, Weiss J N
Department of Medicine, and the Cardiovascular Research Laboratory, UCLA School of Medicine, Los Angeles, California 90095, USA.
J Clin Invest. 1997 Oct 1;100(7):1782-8. doi: 10.1172/JCI119705.
Although a critical factor causing lethal ischemic ventricular arrhythmias, net cellular K loss during myocardial ischemia and hypoxia is poorly understood. We investigated whether selective activation of ATP-sensitive K (KATP) channels causes net cellular K loss by examining the effects of the KATP channel agonist cromakalim on unidirectional K efflux, total tissue K content, and action potential duration (APD) in isolated arterially perfused rabbit interventricular septa. Despite increasing unidirectional K efflux and shortening APD to a comparable degree as hypoxia, cromakalim failed to induce net tissue K loss, ruling out activation of KATP channels as the primary cause of hypoxic K loss. Next, we evaluated a novel hypothesis about the mechanism of hypoxic K loss, namely that net K loss is a passive reflection of intracellular Na gain during hypoxia or ischemia. When the major pathways promoting Na influx were inhibited, net K loss during hypoxia was almost completely eliminated. These findings show that altered Na fluxes are the primary cause of net K loss during hypoxia, and presumably also in ischemia. Given its previously defined role during hypoxia and ischemia in promoting intracellular Ca overload and reperfusion injury, this newly defined role of intracellular Na accumulation as a primary cause of cellular K loss identifies it as a central pathogenetic factor in these settings.
尽管心肌缺血和缺氧期间细胞净钾流失是导致致命性缺血性室性心律失常的关键因素，但其机制仍知之甚少。我们通过研究ATP敏感性钾（KATP）通道激动剂克罗卡林对离体兔室间隔动脉灌注时单向钾外流、组织总钾含量和动作电位时程（APD）的影响，来探究KATP通道的选择性激活是否会导致细胞净钾流失。尽管克罗卡林使单向钾外流增加且APD缩短程度与缺氧时相当，但它未能诱导组织净钾流失，排除了KATP通道激活是缺氧性钾流失的主要原因。接下来，我们评估了一个关于缺氧性钾流失机制的新假说，即净钾流失是缺氧或缺血期间细胞内钠增加的被动反映。当促进钠内流的主要途径被抑制时，缺氧期间的净钾流失几乎完全消除。这些发现表明，钠通量改变是缺氧期间净钾流失的主要原因，缺血时可能也是如此。鉴于其在缺氧和缺血期间促进细胞内钙超载和再灌注损伤的先前定义作用，细胞内钠积累作为细胞钾流失主要原因的这一新定义作用，使其成为这些情况下的核心致病因素。
