Nakata T, Hearse D J, Curtis M J
Department of Pharmacology, King's College, University of London, UK.
J Mol Cell Cardiol. 1990 Aug;22(8):843-58. doi: 10.1016/0022-2828(90)90116-j.
Isolated rat hearts were used to examine whether reperfusion-induced arrhythmias may be caused by washout of substances accumulating during ischemia. This was achieved by subjecting hearts to 10 min of regional ischemia and rendering them transiently inexcitable during the first 1.5 min of reperfusion. Transient inexcitability was induced by switching to cold solution (4 degrees C) shortly before reperfusion (-1.5 min). In controls (no hypothermia), the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) were 83% and 92%, respectively, during the first 1.5 min of reperfusion. Transient hypothermia caused inexcitability and asystole, impaired recovery of coronary flow and abolished VT and VF (all P less than 0.05). On subsequent rewarming to 37 degrees C, coronary flow and sinus rate recovered in all hearts. However, VT and VF occurred in only 58% and 25%, respectively (P less than 0.05). These values were similar to those of new episodes of VT and VF occurring in controls during the equivalent period. Therefore arrhythmias had been abolished during transient hypothermia, not merely delayed. The relative contributions of transient impairment of recovery of coronary flow and transient asystole to the antiarrhythmic effects were examined in a further 10 groups of hearts (n = 12/group) in which reperfusion conditions were transiently manipulated. We utilized combinations of hypothermia, ventricular pacing, acetylcholine (ACh) 55 microM (to cause asystole and impairment of recovery of coronary flow), and right atrial excision and left atrial pacing (to permit bradycardia to be transiently induced during reperfusion by temporarily switching off the pacemaker). The results indicated that transient hypothermia was antiarrhythmic as a result of a reduction of excitability, not because of bradycardia or impairment of recovery of flow. The data support the hypothesis that reperfusion unmasks (disinhibits) latent arrhythmogenic components of ischemia (particularly during the first 1.5 min of reperfusion) and that, by inducing inexcitability, transient hypothermia allows these substances to be washed out without their arrhythmogenic effects being manifested. The identities of the arrhythmogenic and antiarrhythmic substances remain to be determined; we suggest that cyclic AMP and potassium, respectively, are likely candidates.
使用离体大鼠心脏来研究再灌注诱导的心律失常是否可能由缺血期间积累的物质被冲洗掉所引起。这是通过使心脏经历10分钟的局部缺血，并在再灌注的最初1.5分钟内使其暂时失去兴奋性来实现的。在再灌注前（-1.5分钟）不久切换到冷溶液（4℃）来诱导暂时的兴奋性丧失。在对照组（无低温）中，在再灌注的最初1.5分钟内，室性心动过速（VT）和室颤（VF）的发生率分别为83%和92%。短暂低温导致兴奋性丧失和心搏停止，损害冠状动脉血流恢复，并消除VT和VF（所有P<0.05）。随后在所有心脏中重新升温至37℃时，冠状动脉血流和窦性心率恢复。然而，VT和VF的发生率分别仅为58%和25%（P<0.05）。这些值与对照组在同一时期出现的新的VT和VF发作的值相似。因此，心律失常在短暂低温期间被消除，而不仅仅是延迟。在另外10组心脏（每组n = 12）中研究了冠状动脉血流恢复的短暂损害和短暂心搏停止对抗心律失常作用的相对贡献，在这些心脏中对再灌注条件进行了短暂操纵。我们使用了低温、心室起搏、55 microM乙酰胆碱（ACh）（导致心搏停止和冠状动脉血流恢复受损）以及右心房切除和左心房起搏（通过暂时关闭起搏器在再灌注期间允许短暂诱导心动过缓）的组合。结果表明，短暂低温具有抗心律失常作用是由于兴奋性降低，而不是由于心动过缓或血流恢复受损。数据支持这样的假设，即再灌注暴露（解除抑制）了缺血的潜在致心律失常成分（特别是在再灌注的最初1.5分钟内），并且通过诱导兴奋性丧失，短暂低温允许这些物质被冲洗掉而不表现出其致心律失常作用。致心律失常物质和抗心律失常物质的身份仍有待确定；我们认为环磷酸腺苷和钾分别可能是候选物质。
