Limiting sarcolemmal Na+entry during resuscitation from ventricular fibrillation prevents excess mitochondrial Ca2+accumulation and attenuates myocardial injury

Abstract

Background: intracellular Na+accumulation during ischemia and reperfusion leads to cytosolic Ca2+overload through reverse-mode operation of the sarcolemmal Na+-Ca2+exchanger. Cytosolic Ca2+accumulation promotes mitochondrial Ca2+(Ca2+m) overload, leading to mitochondrial injury. We investigated whether limiting sarcolemmal Na+entry during resuscitation from ventricular fibrillation (VF) attenuates Ca2+moverload and lessens myocardial dysfunction in a rat model of VF and closed-chest resuscitation. Methods: hearts were harvested from 10 groups of 6 rats each representing baseline, 15 min of untreated VF, 15 min of VF with chest compression given for the last 5 min (VF/CC), and 60 min postresuscitation (PR). VF/CC and PR included four groups each randomized to receive before starting chest compression the new NHE-1 inhibitor AVE4454B (1.0 mg/kg), the Na+channel blocker lidocaine (5.0 mg/kg), their combination, or vehicle control. The left ventricle was processed for intracellular Na+and Ca2+mmeasurements. Results: limiting sarcolemmal Na+entry attenuated cytosolic Na+increase during VF/CC and the PR phase and prevented Ca2+moverload yielding levels that corresponded to 77% and 71% of control hearts at VF/CC and PR, without differences among specific Na+-limiting interventions. Limiting sarcolemmal Na+entry attenuated reductions in left ventricular compliance during VF and prompted higher mean aortic pressure (110 ± 7 vs. 95 ± 11 mmHg, P < 0.001) and higher cardiac work index (159 ± 34 vs. 126 ± 29 g·m·min−1·kg−1, P < 0.05) with lesser increases in circulating cardiac troponin I at 60 min PR. Conclusions: Na+-limiting interventions prevented excess Ca2+maccumulation induced by ischemia and reperfusion and ameliorated myocardial injury and dysfunction.