E A Sosunov1, E P Anyukhovsky, M R Rosen. 1. Department of Pharmacology and Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Abstract
BACKGROUND: The antiarrhythmic action of quinidine is associated with a slowing of conduction and prolongation of repolarization. The latter effect has no consistent correlation with quinidine actions on action potential duration (APD) in isolated tissue experiments. To enhance our understanding of the mechanisms of quinidine action, we studied its effect on APD in canine epicardial, midmyocardial, and endocardial tissues. METHODS AND RESULTS: Standard microelectrode techniques were used to study the effects of quinidine 2.5 to 20 micromol/L on APD in ventricular epicardial, endocardial, and transmural (M-cell) slabs at cycle lengths (CLs) from 300 to 4000 ms. Qualitatively different time courses of actions and concentration- and rate-dependent effects were seen in M cells compared with the others. In endocardium and epicardium, quinidine induced monotonic and concentration-dependent APD prolongation at all CLs. In contrast, the effects of quinidine in M cells varied from prolongation to shortening, depending on duration of superfusion, concentration, and CL. Experiments with E4031 and TTX suggested that in M cells, quinidine-induced APD lengthening was attributable to block of delayed rectifier potassium current and APD shortening was due to inhibition of TTX-sensitive steady-state sodium current. CONCLUSIONS: In vitro, there is a significant difference of quinidine effects in M cells versus epicardial and endocardial cells that appears to reflect differences in the contributions of specific ion channels to the APD at the three sites. The differences may influence the actions of quinidine on repolarization of the heart in situ and determine both the proarrhythmic and antiarrhythmic actions of the drug.
BACKGROUND: The antiarrhythmic action of quinidine is associated with a slowing of conduction and prolongation of repolarization. The latter effect has no consistent correlation with quinidine actions on action potential duration (APD) in isolated tissue experiments. To enhance our understanding of the mechanisms of quinidine action, we studied its effect on APD in canine epicardial, midmyocardial, and endocardial tissues. METHODS AND RESULTS: Standard microelectrode techniques were used to study the effects of quinidine 2.5 to 20 micromol/L on APD in ventricular epicardial, endocardial, and transmural (M-cell) slabs at cycle lengths (CLs) from 300 to 4000 ms. Qualitatively different time courses of actions and concentration- and rate-dependent effects were seen in M cells compared with the others. In endocardium and epicardium, quinidine induced monotonic and concentration-dependent APD prolongation at all CLs. In contrast, the effects of quinidine in M cells varied from prolongation to shortening, depending on duration of superfusion, concentration, and CL. Experiments with E4031 and TTX suggested that in M cells, quinidine-induced APD lengthening was attributable to block of delayed rectifier potassium current and APD shortening was due to inhibition of TTX-sensitive steady-state sodium current. CONCLUSIONS: In vitro, there is a significant difference of quinidine effects in M cells versus epicardial and endocardial cells that appears to reflect differences in the contributions of specific ion channels to the APD at the three sites. The differences may influence the actions of quinidine on repolarization of the heart in situ and determine both the proarrhythmic and antiarrhythmic actions of the drug.
Authors: Gerard J J Boink; David H Lau; Iryna N Shlapakova; Eugene A Sosunov; Evgeny P Anyukhovsky; Helen E Driessen; Wen Dun; Ming Chen; Peter Danilo; Tove S Rosen; Nazira Őzgen; Heather S Duffy; Yelena Kryukova; Penelope A Boyden; Richard B Robinson; Peter R Brink; Ira S Cohen; Michael R Rosen Journal: Cardiovasc Res Date: 2012-02-27 Impact factor: 10.787
Authors: Ruben Coronel; David H Lau; Eugene A Sosunov; Michiel J Janse; Peter Danilo; Evgeny P Anyukhovsky; Francien J G Wilms-Schopman; Tobias Opthof; Iryna N Shlapakova; Nazira Ozgen; Kevin Prestia; Yelena Kryukova; Ira S Cohen; Richard B Robinson; Michael R Rosen Journal: Heart Rhythm Date: 2010-04-10 Impact factor: 6.343
Authors: Alexey V Glukhov; Vadim V Fedorov; Qing Lou; Vinod K Ravikumar; Paul W Kalish; Richard B Schuessler; Nader Moazami; Igor R Efimov Journal: Circ Res Date: 2010-01-21 Impact factor: 17.367
Authors: David H Lau; Chris Clausen; Eugene A Sosunov; Iryna N Shlapakova; Evgeny P Anyukhovsky; Peter Danilo; Tove S Rosen; Caitlin Kelly; Heather S Duffy; Matthias J Szabolcs; Ming Chen; Richard B Robinson; Jia Lu; Sinhu Kumari; Ira S Cohen; Michael R Rosen Journal: Circulation Date: 2008-12-22 Impact factor: 29.690