Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action

Abstract

Midazolam is a short-acting benzodiazepine that is widely used in anesthesia. Despite its widespread clinical use, detailed information about cardiac side effects of midazolam is largely lacking. Using the double-electrode voltage clamp technique, we studied pharmacological effects of midazolam on heterologously expressed Kv1.5 channels underlying atrial repolarizing current I_Kur. Midazolam dose-dependently inhibited Kv1.5 current, yielding an IC₅₀ of 17 μM in an HEK cell line and an IC₅₀ of 104 μM in Xenopus oocytes. We further showed that midazolam did not affect the half-maximal activation voltage of Kv1.5 channels. However, a small negative shift of the inactivation curve could be observed. Midazolam acted as a typical open-channel inhibitor with rapid onset of block and without frequency dependence of block. Taken together, midazolam is an open channel inhibitor of cardiac Kv1.5 channels. These data add to the current understanding of the pharmacological profile of midazolam.

Keywords:

• anesthetics
• potassium channels
• pharmacology

Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) Scho1350/2-1 Zi1177/1-1 to EPS and EZ. FF was supported by the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology. The skillful assistance of Christine Jeckel is gratefully acknowledged. DS was supported by a grant from the University of Heidelberg: Postdoc Fellowship Program of the Faculty of Medicine.

Disclosure

The authors report no conflicts of interest in this work.