Flunarizine is a Highly Potent Inhibitor of Cardiac hERG Potassium Current

• Published in: Journal of cardiovascular pharmacology Vol. 47; no. 2; pp. 211 - 220
• Main Authors: Trepakova, Elena S, Dech, Spencer J, Salata, Joseph J
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins, Inc 01-02-2006
• Subjects: Animals; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Cell Culture Techniques; Cell Line; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Electrophysiologic Techniques, Cardiac; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - drug effects; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - physiology; Flunarizine - chemistry; Flunarizine - pharmacology; Heart - drug effects; Heart - physiology; Humans; Molecular Structure; Patch-Clamp Techniques; Potassium - metabolism; Potassium Channels, Voltage-Gated - antagonists & inhibitors; Potassium Channels, Voltage-Gated - genetics; Potassium Channels, Voltage-Gated - physiology
• ISSN: 0160-2446; 1533-4023
• DOI: 10.1097/01.fjc.0000200810.18575.80

Flunarizine has been widely used for the management of a variety of disorders such as peripheral vascular diseases, migraine, and epilepsy. The majority of its beneficial effects have been attributed to its ability to inhibit voltage-gated Ca channels in the low micromolar range, albeit non-selectively, as flunarizine has been shown to inhibit a variety of ion channels. We examined the effects of flunarizine on potassium currents through cardiac channels encoded by the human ether-a-go-go related gene (hERG) stably expressed in CHO cells. In this study, we have characterized the effect of flunarizine on biophysical properties of hERG potassium currents with standard whole-cell voltage-clamp techniques. Notably, flunarizine is a highly potent inhibitor of hERG current with an IC50 value of 5.7 nM. The effect of flunarizine on hERG potassium current is concentration and time dependent, and displays voltage dependence over the voltage range between −40 and 0 mV. At concentrations near or above the IC50, flunarizine causes a negative shift in the voltage dependence of hERG current activation and accelerates tail current deactivation. Flunarizine preferentially blocks the activated state of the channel and displays weak frequency dependence of inhibition. Flunarizine also inhibits KCNQ1/KCNE1 channel current with an IC50 of 0.76 μM.