Nitrite Reduces Ischemia-Induced Ventricular Arrhythmias by Attenuating Connexin 43 Dephosphorylation in Rats

Maruyama, Daisuke MD; Hirata, Naoyuki MD, PhD; Tokinaga, Yasuyuki MD, PhD; Kawaguchi, Ryoichi MD; Yamakage, Michiaki MD, PhD

doi: 10.1213/ANE.0000000000001063
Anesthetic Pharmacology: Research Report

BACKGROUND: Ventricular arrhythmias induced by ischemic heart disease are the main cause of sudden cardiac death. Ischemia can cause life-threatening arrhythmias by modulating connexin 43 (Cx43), a principal cardiac gap junction channel protein. The present study investigates whether nitrite can attenuate ischemia-induced ventricular arrhythmias and dephosphorylation of Cx43 in a rat model.

METHODS: Rats were medicated with normal saline (control, n = 10), nitrite (0.015, 0.15, and 1.5 mg/kg, n = 9 or 10 each), and 0.15 mg/kg nitrite with either the nitric oxide scavenger 2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (cPTIO; n = 9) or allopurinol (xanthine oxidoreductase inhibitor, n = 9). We determined the severity of ventricular arrhythmias based on arrhythmia scores and levels of phosphorylated Cx43.

RESULTS: The median arrhythmia score may have been lower in the group given 0.15 mg/kg nitrite (4 [interquartile range {IQR}, 4–5]) than that in the control group (7.5 [IQR, 5.25–8]; P = 0.013). There was no difference among the control, the given 0.015 mg/kg nitrite (7 [IQR, 5–8]), and 1.5 mg/kg nitrite (7 [IQR, 5.5–7.75]; P = 0.95). The arrhythmia scores in the cPTIO (6 [IQR, 5–8]; P = 0.030) and allopurinol (7 [IQR, 5–8]; P = 0.005) groups may have been higher than that in 0.15 mg/kg nitrite group. Immunoblotting revealed that the level of phosphorylated Cx43 in the group given 0.15 mg/kg nitrite, but not in the other treated groups, was significantly higher compared with the control group (P = 0.007).

CONCLUSIONS: Nitrite may have attenuated acute ischemia-induced ventricular arrhythmias and Cx43 dephosphorylation in rats. Nitric oxide, which might be generated by xanthine oxidoreductase via nitrite reduction, appears to play a crucial role in this antiarrhythmic effect.

Published ahead of print October 29, 2015

From the Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.

Accepted for publication September 2, 2015.

Published ahead of print October 29, 2015

Funding: This study was supported by the Japan Society for the Promotion of Science (JSPS; Tokyo, Japan); grant numbers 00438045 and 26861525.

Conflict of Interest: See Disclosures at the end of the article.

This report was previously presented, in part, at the annual meetings of the American Society of Anesthesiologists (ASA) October 12–16, 2013, San Francisco, and October 11–15, 2014, New Orleans.

Reprints will not be available from the authors.

Address correspondence to Naoyuki Hirata, MD, PhD, Department of Anesthesiology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan. Address e-mail to

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