Abstract 69: Post-Resuscitation Mitochondrial Ca2+ Overload is Prevented by Limiting Sarcolemmal Na+ Entry During Resuscitation from Ventricular Fibrillation
Background: Intracellular Na+ accumulation during ischemia/reperfusion leads to cytosolic Ca2+ overload via reverse mode operation of the sarcolemmal Na+-Ca2+ exchanger. Cytosolic Ca2+ accumulation promotes mitochondrial Ca2+ (Ca2+m) overload leading to mitochondrial injury and apoptosis. We investigated whether interventions that limit sarcolemmal Na+ entry during resuscitation from ventricular fibrillation (VF) attenuate Ca2+m overload in a rat model of VF and closed-chest resuscitation.
Methods: Hearts were harvested from 10 groups of 6 rats each representing baseline (BL), 15 mins of untreated VF, 15 mins of VF plus chest compression for the last 5 mins (CC), and 60 mins post-resuscitation (PR). CC and PR included 4 groups each randomized to receive immediately before starting chest compression the new NHE-1 inhibitor AVE4454 (1.0 mg/kg), the Na+ channel blocker lidocaine (5.0 mg/kg), the combination of AVE4454 and lidocaine (A/L), or vehicle control. Mitochondria were isolated from left ventricular tissue and Ca2+m measured using graphite furnace atomic absorption spectrometry at 422.7 nm after acid digestion.
Results: In control hearts, Ca2+m during CC was similar to BL and VF levels but increased by ≈ 40% at 60 mins PR. Na+-limiting interventions prevented Ca2+m overload yielding Ca2+m that corresponded to 77% and 71% of CC and PR control hearts, without differences among Na+-limiting groups (Figure⇓). Limiting Ca2+m overload was associated with improved PR cardiac work index (159 ± 34 vs 126 ± 29 g·m/min/kg, p < 0.05).
Conclusions: Na+-limiting interventions prevented mitochondrial Ca2+ overload and ameliorated post-resuscitation myocardial dysfunction.