Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action

摘要: 1 We studied the effects of ranolazine, an antianginal agent with promise as antiarrhythmic drug, on wild-type (WT) and long QT syndrome variant 3 (LQT-3) mutant Na(+) channels expressed in human embryonic kidney (HEK) 293 cells knock-in mouse cardiomyocytes used site-directed mutagenesis to probe site action drug. 2 find preferential ranolazine block sustained vs peak channel current for LQT-3 (DeltaKPQ Y1795C) (IC(50)=15 135 microM) similar results obtained HEK myocytes. Ranolazine both is significantly reduced by mutation (F1760A) a single residue previously shown contribute critically binding local anesthetic (LA) molecules channel. 4 decreases potential duration (APD) at 50 90% repolarization 23+/-5 27+/-3%, respectively, DeltaKPQ ventricular myocytes but has little effect APD WT 5 Computational modeling cardiac myocyte electrical activity that incorporates our voltage-clamp data predicts marked ranolazine-induced shortening expressing channels. 6 Our demonstrate first time utility blocker induced inherited mutations cause disease further, these are very likely due interactions receptor LA sodium