Bethell H W, Vandenberg J I, Smith G A, Grace A A
Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
Am J Physiol. 1998 Aug;275(2):H551-61. doi: 10.1152/ajpheart.1998.275.2.H551.
Myocardial ischemia, primarily a metabolic insult, is also defined by altered cardiac mechanical and electrical activity. We have investigated the metabolic contributions to the electrophysiological changes during low-flow ischemia (7.5% of the control flow) using 31P NMR spectroscopy to monitor metabolic parameters, suction electrodes to study epicardial monophasic action potentials, and 86Rb as a tracer for K+-equivalent efflux during low-flow ischemia in the Langendorff-perfused ferret heart. Shortening of the action potential duration at 90% repolarization (APD90) was most marked between 1 and 5 min after induction of ischemia, at which time it shortened from 261 +/- 4 to 213 +/- 8 ms. The period of marked APD90 shortening was accompanied by a fivefold increase in the rate of 86Rb efflux, both of which were inhibited by the ATP-sensitive K+ (KATP)-channel blockers glibenclamide and 5-hydroxydecanoate (5-HD), as well as by a significant fall in intracellular pH (pHi) from 7.14 +/- 0.02 to 6.83 +/- 0.03 but no change in intracellular ATP concentration ([ATP]i). We therefore investigated whether a fall in pHi could be the metabolic change responsible for modulating cardiac KATP channel activity in the intact heart during ischemia. Both metabolic (30 mM lactate added to extracellular solution) and respiratory (PCO2 increased to 15%) acidosis caused an initial lengthening of APD90 to 112 +/- 1.5 and 113 +/- 0.9%, respectively, followed by shortening during continued acidosis to 106 +/- 1.2 and 106 +/- 1.4%, respectively. The shortening of APD90 during continued acidosis was inhibited by glibenclamide, consistent with acidosis causing activation of KATP channels at normal [ATP]i. The similar responses to metabolic (induced by adding either l- or d-lactate) and respiratory acidosis suggest that lactate has no independent metabolic effect on action potential repolarization.
心肌缺血主要是一种代谢损伤，也可由心脏机械和电活动的改变来定义。我们使用31P核磁共振波谱来监测代谢参数，用吸电极研究心外膜单相动作电位，并以86Rb作为低流量缺血期间钾离子等效外流的示踪剂，研究了低流量缺血（对照流量的7.5%）期间代谢对电生理变化的影响，实验对象为Langendorff灌注的雪貂心脏。在缺血诱导后1至5分钟内，90%复极化时动作电位时程（APD90）的缩短最为明显，此时它从261±4毫秒缩短至213±8毫秒。APD90显著缩短的时期伴随着86Rb外流速率增加了五倍，这两者均受到ATP敏感性钾（KATP）通道阻滞剂格列本脲和5-羟基癸酸（5-HD）的抑制，同时细胞内pH值（pHi）从7.14±0.02显著降至6.83±0.03，但细胞内ATP浓度（[ATP]i）没有变化。因此，我们研究了pHi的下降是否可能是缺血期间完整心脏中调节心脏KATP通道活性的代谢变化。代谢性酸中毒（向细胞外溶液中添加30 mM乳酸）和呼吸性酸中毒（PCO2增加至15%）均导致APD90最初分别延长至112±1.5%和113±0.9%，随后在持续酸中毒期间分别缩短至106±1.2%和106±1.4%。持续酸中毒期间APD90的缩短受到格列本脲的抑制，这与酸中毒在正常[ATP]i时导致KATP通道激活一致。对代谢性酸中毒（添加l-或d-乳酸诱导）和呼吸性酸中毒的类似反应表明乳酸对动作电位复极化没有独立的代谢作用。
