Mitochondrial depolarization and asystole in the globally ischemic rabbit heart: coordinated response to interventions affecting energy balance

作者：Venable Paul W; Sciuto Katie J; Warren Mark; Taylor Tyson G; Garg Vivek; Shibayama Junko; Zaitsev Alexey V^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2015, 308(5): H485-H499.

DOI：10.1152/ajpheart.00257.2014

• myocardial ischemia
• mitochondrial depolarization
• ATP-sensitive potassium channel
• asystole
• blebbistatin

Mitochondrial membrane potential (Delta Psi(m)) depolarization has been implicated in the loss of excitability (asystole) during global ischemia, which is relevant for the success of defibrillation and resuscitation after cardiac arrest. However, the relationship between Delta Psi(m) depolarization and asystole during no-flow ischemia remains unknown. We applied spatial Fourier analysis to confocally recorded fluorescence emitted by Delta Psi(m)-sensitive dye tetramethylrhodamine methyl ester. The time of ischemic Delta Psi(m) depolarization (t(mito_depol)) was defined as the time of 50% decrease in the magnitude of spectral peaks reflecting Delta Psi(m). The time of asystole (t(asys)) was determined as the time when spontaneous and induced ventricular activity ceased to exist. Interventions included tachypacing (150 ms), myosin II ATPase inhibitor blebbistatin (heart immobilizer), and the combination of blebbistatin and the inhibitor of glycolysis iodoacetate. In the absence of blebbistatin, confocal images were obtained during brief perfusion with hyperkalemic solution and after the contraction failed between 7 and 15 min of ischemia. In control, t(mito_depol) and t(asys) were 24.4 +/- 6.0 and 26.0 +/- 5.0 min, respectively. Tachypacing did not significantly affect either parameter. Blebbistatin dramatically delayed t(mito_depol) and t(asys) (51.4 +/- 8.6 and 45.7 +/- 5.3 min, respectively; both P < 0.0001 vs. control). Iodoacetate combined with blebbistatin accelerated both events (t(mito_depol), 12.7 +/- 1.8 min; and t(asys), 6.5 +/- 1.1 min; both P < 0.03 vs. control). In all groups pooled together, t(asys) was strongly correlated with t(mito_depol) (R-2 = 0.845; P < 0.0001). These data may indicate a causal relationship between Delta Psi(m) depolarization and asystole or a similar dependence of the two events on energy depletion during ischemia. Our results urge caution against the use of blebbistatin in studies addressing pathophysiology of myocardial ischemia.

• 出版日期2015-3-1