RT Journal Article
SR Electronic
T1 Facilitation of hERG channels by blockers: a mechanism predicted to reduce lethal cardiac arrhythmias
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 341875
DO 10.1101/341875
A1 Kazuharu Furutani
A1 Kunichika Tsumoto
A1 I-Shan Chen
A1 Kenichiro Handa
A1 Yuko Yamakawa
A1 Jon T. Sack
A1 Yoshihisa Kurachi
YR 2018
UL http://biorxiv.org/content/early/2018/06/08/341875.abstract
AB Fatal cardiac arrhythmias are caused by some, but not all, drugs that inhibit the cardiac rapid delayed-rectifier current (IKr) by blocking hERG channels. Here, we propose a novel mechanism that could make certain hERG blockers less proarrhythmic. Several drugs that block hERG channels, yet have favorable cardiac safety profiles, also evoke another effect; they increase the current amplitude upon low-voltage depolarization (facilitation). Voltage-clamp recordings of hERG block and facilitation by nifekalant, a Class III antiarrhythmic agent, constrained a model of human cardiac IKr. In human ventricular action potential simulations, nifekalant showed its therapeutic ability to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evoked early afterdepolarizations, which cause lethal arrhythmias. Facilitation prevented early afterdepolarizations at the same degree of block by increasing IKr during repolarization phase of action potentials. Thus, facilitation is proposed to reduce the arrhythmogenic risk of hERG blockers.Abbreviations AP: action potential; APD: action potential duration; APD90: action potential duration measured at 90% repolarization; EAD: early afterdepolarization; hERG: human ether-ago-go-related gene; ICaL: L-type Ca2+ channel current; Inet: net ionic current; IK1: inward-rectifier potassium current; IKr: rapid component of the delayed-rectifier potassium current; INa: sodium current; ORd: O’Hara-Rudy dynamic