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Clinical Concentrations of Local Anesthetics Bupivacaine and Lidocaine Differentially Inhibit Human Kir2.x Inward Rectifier K+ Channels

Nakahira, Kei MD; Oshita, Kensuke MD, PhD; Itoh, Masayuki PhD; Takano, Makoto MD, PhD; Sakaguchi, Yoshiro MD, PhD; Ishihara, Keiko MD, PhD

doi: 10.1213/ANE.0000000000001137
Anesthetic Pharmacology: Research Report

BACKGROUND: Inward rectifier K+ channels of the Kir2.x subfamily are widely expressed in neuronal tissues, controlling neuronal excitability. Previous studies reported that local anesthetics (LAs) do not affect Kir2 channels. However, the effects have not been studied at large concentrations used in regional anesthesia.

METHODS: This study used the patch-clamp technique to examine the effects of bupivacaine and lidocaine on Kir2.1, Kir2.2, and Kir2.3 channels expressed in human embryonic kidney 293 cells.

RESULTS: When applied extracellularly in whole-cell recordings, both LAs inhibited Kir2.x currents in a voltage-independent manner. Inhibition with bupivacaine was slow and irreversible, whereas that with lidocaine was fast and reversible. Kir2.3 displayed a greater sensitivity to bupivacaine than Kir2.1 and Kir2.2 (50% inhibitory concentrations at approximately 5 minutes, 0.6 vs 8–10 mM), whereas their sensitivities to lidocaine were similar (50% inhibitory concentrations, 1.5–2.7 mM). Increases in the charged/neutral ratio of the LAs at an acidic extracellular pH attenuated their inhibitory effects, and a permanently charged lidocaine derivative QX-314 exhibited no effects when applied extracellularly. Inside-out experiments demonstrated that inhibition of Kir2.1 with cytoplasmic lidocaine and QX-314 was rapid and reversible, whereas that induced by bupivacaine was slow and irreversible. Furthermore, dose-inhibition relations for the charged form of bupivacaine and lidocaine obtained at different cytoplasmic pHs could be approximated by a single relation for each LA.

CONCLUSIONS: The results indicate that both LAs at clinical concentrations equilibrated rapidly with the intracellular milieu, differentially inhibiting Kir2.x channel function from the cytoplasmic side.

Published ahead of print January 11, 2016

From the *Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Saga University, Saga, Japan; and Department of Physiology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.

Kei Nakahira, MD, is currently affiliated with the Oda Regional Medical Center, Kashima, Saga, Japan.

Kensuke Oshita, MD, PhD, is currently affiliated with the Department of Anesthesiology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.

Accepted for publication November 3, 2015.

Published ahead of print January 11, 2016

Funding: Support was provided by funding from Saga University, Japan, and Kurume University, Japan. This research was also supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 22590208 to KI.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

This report was previously presented, in part, at the 60th Annual Meeting of the Japanese Society of Anesthesiologists, and at the 90th Annual Meeting of the Physiological Society of Japan.

Reprints will not be available from the authors.

Address correspondence to Keiko Ishihara, MD, PhD, Department of Physiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. Address e-mail to keikoiy@med.kurume-u.ac.jp.

© 2016 International Anesthesia Research Society