Ranolazine preferentially blocked sustained versus peak Na+ channel current in LQT-3 mutant channels (IC50 15 vs 135 microM) and decreased action potential duration in mutant but not wild-type cells.
Does ranolazine block sustained Na+ channel current and shorten action potential duration in LQT-3 mutant models?
Ranolazine preferentially blocks sustained Na+ channel current and shortens action potential duration in LQT-3 mutant models, likely via interaction with the local anesthetic receptor site.
1 We studied the effects of ranolazine, an antianginal agent with promise as an 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 and knock-in mouse cardiomyocytes and used site-directed mutagenesis to probe the site of action of the drug. 2 We find preferential ranolazine block of sustained vs peak Na(+) channel current for LQT-3 mutant (DeltaKPQ and Y1795C) channels (IC(50)=15 vs 135 microM) with similar results obtained in HEK 293 cells and knock-in myocytes. 3 Ranolazine block of both peak and sustained Na(+) channel current is significantly reduced by mutation (F1760A) of a single residue previously shown to contribute critically to the binding site for local anesthetic (LA) molecules in the Na(+) channel. 4 Ranolazine significantly decreases action potential duration (APD) at 50 and 90% repolarization by 23+/-5 and 27+/-3%, respectively, in DeltaKPQ mouse ventricular myocytes but has little effect on APD of WT myocytes. 5 Computational modeling of human cardiac myocyte electrical activity that incorporates our voltage-clamp data predicts marked ranolazine-induced APD shortening in cells expressing LQT-3 mutant channels. 6 Our results demonstrate for the first time the utility of ranolazine as a blocker of sustained Na(+) channel activity induced by inherited mutations that cause human disease and further, that these effects are very likely due to interactions of ranolazine with the receptor site for LA molecules in the sodium channel.
Fredj et al. (Mon,) conducted a other in Long QT syndrome variant 3 (LQT-3). Ranolazine vs. Wild-type (WT) channels/myocytes was evaluated on Na(+) channel current block and action potential duration. Ranolazine preferentially blocked sustained versus peak Na+ channel current in LQT-3 mutant channels (IC50 15 vs 135 microM) and decreased action potential duration in mutant but not wild-type cells.