Abstract 13390: Nitrite Ameliorates Sepsis-Induced Myocardial Dysfunction via Mitochondrial Protection
Introduction: Mitochondrial impairment plays an important role in septic myocardial dysfunction. Several studies have shown that nitrite can ameliorate myocardial ischemia-reperfusion injury via mitochondrial protection. However, the effect of nitrite on septic myocardium has not been investigated in detail.
Hypothesis: Nitrite therapy will improve cardiac contractility via mitochondrial function in a murine model of polymicrobial sepsis.
Methods: Sepsis was induced in Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered saline (NS group, n=8) or saline with nitrite (Nit group, n=8) subcutaneously. No procedure was performed in the control group. First, to determine the most effective dose of nitrite in septic rats, we administered different doses of nitrite (0.1, 0.3, 1, 3, 10 mg/kg) and examined cardiac function in an isolated heart experiment after 8 hours. The most effective dose of nitrite (1 mg/kg) was used in subsequent experiments. For an in vitro study, hearts were removed and cardiac mitochondria were isolated by differential centrifugation. We measured mitochondrial oxygen consumption and determined the respiratory control ratio (RCR). We also assessed protein expression by ELISA and immunoblotting.
Results: In the isolated heart experiment, left ventricular developed pressure in the Nit group (dose of 1 mg/kg) was significantly higher than that in the NS group (Fig. 1). Although RCR in the NS group was significantly decreased compared to that in control group, RCR in the Nit group was preserved (Fig. 2). Myocardial nitrotyrosine levels were comparable in the NS group and the Nit group. In the Nit group, Akt phosphorylation was preserved and activation of NF-κB was inhibited.
Conclusions: Nitrite therapy preserved mitochondrial oxidative phosphorylation in the septic myocardium and improved contractility. Nitrite affects the stress response signaling pathway and may be novel treatment for septic myocardial dysfunction.
Author Disclosures: R. Kawaguchi: None. N. Hirata: None. Y. Yoshikawa: None. T. Chaki: None. M. Yamakage: None.
- © 2015 by American Heart Association, Inc.