Limiting sarcolemmal Na super(+) entry during resuscitation from ventricular fibrillation prevents excess mitochondrial Ca super(2+) accumulation and attenuates myocardial injury

• Published in: Journal of applied physiology (1985) Vol. 103; no. 1; pp. 55 - 65
• Main Authors: Wang, Sufen, Radhakrishnan, Jeejabai, Ayoub, Iyad M, Kolarova, Julieta D, Taglieri, Domenico M, Gazmuri, Raul J
• Format: Journal Article
• Language: English
• Published: 01.07.2007
• ISSN: 8750-7587

Background: intracellular Na super(+) accumulation during ischemia and reperfusion leads to cytosolic Ca super(2+) overload through reverse-mode operation of the sarcolemmal Na super(+)-Ca super(2+) exchanger. Cytosolic Ca super(2+) accumulation promotes mitochondrial Ca super(2+) (Ca super(2+) sub(m)) overload, leading to mitochondrial injury. We investigated whether limiting sarcolemmal Na super(+) entry during resuscitation from ventricular fibrillation (VF) attenuates Ca super(2+) sub(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 super(+) channel blocker lidocaine (5.0 mg/kg), their combination, or vehicle control. The left ventricle was processed for intracellular Na super(+) and Ca super(2+) sub(m) measurements. Results: limiting sarcolemmal Na super(+) entry attenuated cytosolic Na super(+) increase during VF/CC and the PR phase and prevented Ca super(2+) sub(m) overload yielding levels that corresponded to 77% and 71% of control hearts at VF/CC and PR, without differences among specific Na super(+)-limiting interventions. Limiting sarcolemmal Na super(+) entry attenuated reductions in left ventricular compliance during VF and prompted higher mean aortic pressure (110 plus or minus 7 vs. 95 plus or minus 11 mmHg, P < 0.001) and higher cardiac work index (159 plus or minus 34 vs. 126 plus or minus 29 g.m.min super(-1).kg super(-1), P < 0.05) with lesser increases in circulating cardiac troponin I at 60 min PR. Conclusions: Na super(+)-limiting interventions prevented excess Ca super(2+) sub(m) accumulation induced by ischemia and reperfusion and ameliorated myocardial injury and dysfunction.