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

Department of Medicine, Division of Critical Care Medicine, and Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science; and Medical Service, Section of Critical Care Medicine, North Chicago Veterans Affairs Medical Center, North Chicago, Illinois

Submitted 16 October 2006 ; accepted in final form 11 April 2007

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⁺_m overload 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⁺_m measurements. Results: limiting sarcolemmal Na⁺ entry attenuated cytosolic Na⁺ increase during VF/CC and the PR phase and prevented Ca²⁺_m overload 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⁺_m accumulation induced by ischemia and reperfusion and ameliorated myocardial injury and dysfunction.

calcium; cardiopulmonary resuscitation; myocardial ischemia; sodium

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