Flunarizine is a highly potent inhibitor of cardiac hERG potassium current.
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 Ca2+ 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 microM.
Department of Preclinical Strategy and Safety Evaluation, Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. elena_trepakova@merck.com
Elena S
ES
Trepakova
Spencer J
SJ
Dech
Joseph J
JJ
Salata
D000818:Animals; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002460:Cell Line; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D022062:Electrophysiologic Techniques, Cardiac; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005444:Flunarizine / Q000737:chemistry / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
D002121:Calcium Channel Blockers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; D005444:Flunarizine; D011188:Potassium