Facilitation of hERG channels by blockers: a mechanism predicted to reduce lethal cardiac arrhythmias

Fatal cardiac arrhythmias are caused by some, but not all, drugs that inhibit the cardiac rapid delayed-rectifier current ( I Kr ) 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 I Kr . In human ventricular action potential simulations, nifekalant showed its therapeutic ability to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evoked early afterdepolarizations, which cause lethal arrhythmias. Facilitation prevented early afterdepolarizations at the same degree of block by increasing I Kr 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; APD 90 : action potential duration measured at 90% repolarization; EAD: early afterdepolarization; hERG: human ether-ago-go-related gene; I CaL : L-type Ca 2+ channel current; I net : net ionic current; I K1 : inward-rectifier potassium current; I Kr : rapid component of the delayed-rectifier potassium current; I Na : sodium current; ORd: O’Hara-Rudy dynamic