Pharmacologically induced long QT type 2 can be rescued by activation of IKs with benzodiazepine R-L3 in isolated guinea pig cardiomyocytes.
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.
Nissen
Jakob Dahl
JD
Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Diness
Jonas Goldin
JG
Diness
Thomas Goldin
TG
Hansen
Rie Schultz
RS
Grunnet
Morten
M
Jespersen
Thomas
T
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
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; C113498:L 364373; D001569:Benzodiazepines