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Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses

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Abstract

Purpose

A specific therapeutic strategy in sepsis-induced myocardial dysfunction remains to be determined. Nitrite may have cardioprotective effects against sepsis-induced myocardial dysfunction. This study investigated the cardioprotective effects of nitrite on myocardial function, mitochondrial bioenergetics, and its underlying molecular mechanisms in severe septic rats.

Methods

Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered normal saline (NS group) or nitrite (nitrite group) subcutaneously. We administered nitrite at different doses (0.1–10 mg/kg) to ascertain the most effective dose and examined cardiac function in an isolated heart experiment 8 h after CLP. We investigated mitochondrial bioenergetics and molecular mechanisms underlying the administration of nitrite in vitro.

Results

In isolated heart experiments, the left ventricular developed pressure (96 ± 5 mmHg) at a moderate nitrite dose (1.0 mg/kg) was significantly higher than that in the NS group (75 ± 4 mmHg, P < 0.05). Mitochondrial oxidative phosphorylation in the nitrite group was significantly higher than that in the NS group (P < 0.01). Immunoblotting revealed that nitrite significantly increased the phosphorylation of Akt (P < 0.05) and reduced the nuclear translocation of NF-κB (P < 0.05) compared with the NS group. Nitrite was also shown to improve the rate of survival in severe septic rats (P < 0.001).

Conclusions

Our results showed that a moderate nitrite dose improved septic myocardial dysfunction at organ, cellular, and molecular levels via modulation of stress signal responses, which resulted in an improvement in survival.

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Funding

This work was supported in part by the Japan Society for the Promotion of Science (JSPS; Tokyo, Japan); Grant Nos. 25861724 and 15K20348.

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Authors and Affiliations

  1. Department of Anesthesiology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan

    Ryoichi Kawaguchi, Naoyuki Hirata, Yasuyuki Tokinaga, Shunsuke Hayashi & Michiaki Yamakage

  2. Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

    Shigeaki Inoue & Nobuo Watanabe

Authors
  1. Ryoichi Kawaguchi
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  2. Naoyuki Hirata
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  3. Yasuyuki Tokinaga
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  4. Shunsuke Hayashi
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Correspondence to Naoyuki Hirata.

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Kawaguchi, R., Hirata, N., Tokinaga, Y. et al. Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses. J Anesth 31, 885–894 (2017). https://doi.org/10.1007/s00540-017-2417-0

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  • DOI: https://doi.org/10.1007/s00540-017-2417-0

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