Abstract 12745: Amelioration of Mitochondrial Injury During Cardiac Resuscitation by the Combined Administration of α-Methylnorepinephrine and Zoniporide

Abstract

Introduction: We have shown in a rat model of VF and closed-chest resuscitation that plasma levels of cytochrome c - a marker of mitochondrial injury - are inversely related to survival and both influenced by interventions that attenuate mitochondrial injury. We have also shown that administration of zoniporide (ZNP) - an NHE-1 inhibitor - combined with α-methylnorepinephrine (α-MNE) - a peripheral selective α2-adrenoreceptor agonist is highly effective for resuscitation. Hypothesis: We hypothesized that the ZNP/α-MNE combination exerts its beneficial effects partly by attenuating mitochondrial injury. Methods: VF was electrically induced in 48 male retired breeder rats and left untreated for 8 minutes. Resuscitation was attempted by 8 minutes of chest compression and delivery of electrical shocks. Rats were randomized 1:1:1:1 to receive a 3 mg/kg bolus of ZNP or 0.9% NaCl before chest compression and a 100 μg/kg bolus of α-MNE or its vehicle at minute 2 of chest compression establishing 4 groups of 12 rats each. Successfully resuscitated rats were monitored for 240 minutes. Plasma cytochrome c levels were measured by an electrochemiluminescence (ECL) immunoassay developed by us using antibodies provided in a DuoSet IC, Rat/Mouse Total Cytochrome c kit (R&D systems). The ECL signal was measured using a QuickPlex SQ 120 multiplex imager from MesoScale Discovery (MSD). Results: Post-Resuscitation (PR) plasma cytochrome c levels (fold increase over baseline) were markedly attenuated in groups that received ZNP demonstrating statistical significance at PR 180 minutes (Figure). Cytochrome c levels were positively correlated with lactate levels and marginally negatively correlated with cardiac work index at PR 180 (Figure). PR lactate levels were reduced in all treatment groups with the greatest effect by the ZNP/α-MNE combination. Conclusions: We confirm that the ZNP/α-MNE combination exerts resuscitation benefits by ameliorating mitochondrial injury.