kn-93 and Brugada-Syndrome

Ventricular arrhythmias commonly originate from the right ventricular out-flow tract (RVOT). However, the electrophysiological characteristics and Ca(2+) homoeostasis of RVOT cardiomyocytes remain unclear. Whole-cell patch clamp and indo-1 fluorometric ratio techniques were used to investigate action potentials, Ca(2+) homoeostasis and ionic currents in isolated cardiomyocytes from the rabbit RVOT and right ventricular apex (RVA). Conventional microelectrodes were used to record the electrical activity before and after (KN-93, a Ca(2+) /calmodulin-dependent kinase II inhibitor, or ranolazine, a late sodium current inhibitor) treatment in RVOT and RVA tissue preparations under electrical pacing and ouabain (Na(+) /K(+) ATPase inhibitor) administration. In contrast to RVA cardiomyocytes, RVOT cardiomyocytes were characterized by longer action potential duration measured at 90% and 50% repolarization, larger Ca(2+) transients, higher Ca(2+) stores, higher late Na(+) and transient outward K(+) currents, but smaller delayed rectifier K(+) , L-type Ca(2+) currents and Na(+) -Ca(2+) exchanger currents. RVOT cardiomyocytes showed significantly more pacing-induced delayed afterdepolarizations (22% versus 0%, P < 0.05) and ouabain-induced ventricular arrhythmias (94% versus 61%, P < 0.05) than RVA cardiomyocytes. Consistently, it took longer time (9 ± 1 versus 4 ± 1 min., P < 0.05) to eliminate ouabain-induced ventricular arrhythmias after application of KN-93 (but not ranolazine) in the RVOT in comparison with the RVA. These results indicate that RVOT cardiomyocytes have distinct electrophysiological characteristics with longer AP duration and greater Ca(2+) content, which could contribute to the high RVOT arrhythmogenic activity.

Topics: Acetanilides; Action Potentials; Animals; Arrhythmias, Cardiac; Benzylamines; Brugada Syndrome; Calcium; Cardiac Conduction System Disease; Electrophysiological Phenomena; Enzyme Inhibitors; Heart Conduction System; Heart Ventricles; Myocytes, Cardiac; Patch-Clamp Techniques; Piperazines; Protein Kinase Inhibitors; Rabbits; Ranolazine; Sodium-Calcium Exchanger; Sulfonamides