Balasubramaniam Richard, Chawla Sangeeta, Grace Andrew A, Huang Christopher L-H
Physiological Laboratory, University of Cambridge, Downing St., Cambridge, CB2 3EG, U.K.
Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1584-93. doi: 10.1152/ajpheart.01250.2004. Epub 2005 May 27.
Heart failure leading to ventricular arrhythmogenesis is a major cause of clinical mortality and has been associated with a leak of sarcoplasmic reticular Ca(2+) into the cytosol due to increased open probabilities in cardiac ryanodine receptor Ca(2+)-release channels. Caffeine similarly increases such open probabilities, and so we explored its arrhythmogenic effects on intact murine hearts. A clinically established programmed electrical stimulation protocol adapted for studies of isolated intact mouse hearts demonstrated that caffeine (1 mM) increased the frequency of ventricular tachycardia from 0 to 100% yet left electrogram duration and latency unchanged during programmed electrical stimulation, thereby excluding slowed conduction as a cause of arrhythmogenesis. We then used fluorescence measurements of intracellular Ca(2+) concentration in isolated mouse ventricular cells to investigate parallel changes in Ca(2+) homeostasis associated with these arrhythmias. Both caffeine (1 mM) and FK506 (30 microM) reduced electrically evoked cytosolic Ca(2+) transients yet increased the frequency of spontaneous Ca(2+)-release events. Diltiazem (1 microM) but not nifedipine (1 microM) pretreatment suppressed these increases in frequency. Identical concentrations of diltiazem but not nifedipine correspondingly suppressed the arrhythmogenic effects of caffeine in whole hearts. These findings thus directly implicate spontaneous Ca(2+) waves in triggered arrhythmogenesis in intact hearts.
导致心室心律失常的心力衰竭是临床死亡的主要原因，并且与肌浆网Ca(2+)因心脏雷诺丁受体Ca(2+)释放通道开放概率增加而泄漏到细胞质中有关。咖啡因同样会增加这种开放概率，因此我们探究了其对完整小鼠心脏的致心律失常作用。一种适用于分离的完整小鼠心脏研究的临床既定程序电刺激方案表明，咖啡因（1 mM）可使室性心动过速的频率从0增加到100%，但在程序电刺激期间电活动图持续时间和潜伏期不变，从而排除了传导减慢作为心律失常发生原因的可能性。然后，我们使用荧光测量分离的小鼠心室细胞内Ca(2+)浓度，以研究与这些心律失常相关的Ca(2+)稳态的平行变化。咖啡因（1 mM）和FK506（30 microM）均降低了电诱发的细胞质Ca(2+)瞬变，但增加了自发Ca(2+)释放事件的频率。地尔硫卓（1 microM）而非硝苯地平（1 microM）预处理可抑制这些频率增加。相同浓度的地尔硫卓而非硝苯地平相应地抑制了咖啡因在全心中的致心律失常作用。因此，这些发现直接表明自发Ca(2+)波在完整心脏的触发心律失常中起作用。
