title: Pharmacologically induced long QT type 2 can be rescued by activation of IKs with benzodiazepine R-L3 in isolated guinea pig cardiomyocytes.
abstract: The ionic current responsible for terminating the action potential (AP), and thereby in part determining the AP duration (APD), is the potassium current (IK), consisting of primarily two components: a rapidly (IKr) and a slowly (IKs) activating delayed rectifier potassium current. The aim of this study was to evaluate potential antiarrhythmic effects of compound induced IKs activation using the benzodiazepine L-364,373 (R-L3). Ventricular myocytes from guinea pigs were isolated and whole-cell current clamping was performed at 35 degrees C. It was found that 1 microM R-L3 significantly reduced the APD90 at pacing frequencies of 1, 2, and 4 Hz when compared to control (40 +/- 6%, 22 +/- 2%, and 32 +/- 2%, respectively). The reduction of APD90 was accompanied by a reduced triangulation (given as APD30-90) when compared to control at all pacing frequencies (62 +/- 7 ms vs. 41 +/- 3 ms, 55 +/- 5 ms vs. 35 +/- 6 ms, and 45 +/- 4 ms vs. 32 +/- 2 ms, at 1 Hz, 2 Hz, and 4 Hz, respectively). The abbreviated APDs also resulted in a reduction in the relative refractory period, and no direct protection against pacing induced early after-depolarizations (EAD) could be observed. However, an increase in repolarizing capacity was seen with 1 microM R-L3, as more complete repolarization of the AP was achieved before EADs could be elicited. Finally, a functional demonstration of the repolarization reserve revealed that increased IKs can counteract a pharmacologically reduced IKr. In conclusion, pharmacological activation of IKs possesses both pro- and antiarrhythmic characters. The most prominent antiarrhythmic propensity is the ability for IKs activation to rescue a cellular model of long QT type 2.
authors: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Jakob Dahl
authors: JD
authors: Nissen
authors: Jonas Goldin
authors: JG
authors: Diness
authors: Thomas Goldin
authors: TG
authors: Diness
authors: Rie Schultz
authors: RS
authors: Hansen
authors: Morten
authors: M
authors: Grunnet
authors: Thomas
authors: T
authors: Jespersen
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000378:metabolism; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; C113498:L 364373; D001569:Benzodiazepines