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

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-[kappa]B (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.
Author(s): Ryoichi Kawaguchi [sup.1] , Naoyuki Hirata [sup.1] , Yasuyuki Tokinaga [sup.1] , Shunsuke Hayashi [sup.1] , Shigeaki Inoue [sup.2] , Nobuo Watanabe [sup.2] , Michiaki Yamakage [sup.1] Author Affiliations: [...]