A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials

[Display omitted] A loss of repolarization reserve due to downregulation of K+ currents has been observed in cultured ventricular myocytes. A similar reduction of K+ currents is well documented under numerous pathophysiological conditions. We examined the extent of K+ current downregulation in cultu...

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Bibliographic Details
Published in:Biochemical pharmacology 2016-05, Vol.108, p.36-46
Main Authors: Calloe, Kirstine, Di Diego, José M., Hansen, Rie Schultz, Nagle, Shea A., Treat, Jacqueline A., Cordeiro, Jonathan M.
Format: Article
Language:English
Subjects:
Action potential repolarization
Action Potentials
Animals
Cells, Cultured
Cultured cells
Dogs
Electrophysiology
Female
Heart Ventricles - cytology
Male
Muscle Cells - drug effects
Muscle Cells - physiology
Myocardium - cytology
NS3623
Phenylurea Compounds - pharmacology
Potassium Channels - physiology
Repolarization reserve
Tetrazoles - pharmacology
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Summary:[Display omitted] A loss of repolarization reserve due to downregulation of K+ currents has been observed in cultured ventricular myocytes. A similar reduction of K+ currents is well documented under numerous pathophysiological conditions. We examined the extent of K+ current downregulation in cultured canine cardiac myocytes and determined whether a dual K+ current activator can normalize K+ currents and restore action potential (AP) configuration. Ventricular myocytes were isolated and cultured for up to 48h. Current and voltage clamp recordings were made using patch electrodes. Application of NS3623 to coronary-perfused left ventricular wedges resulted in increased phase 1 magnitude, epicardial AP notch and J wave amplitude. Patch clamp measurements of IKr and Ito revealed an increase in the magnitude of both currents. Culturing of Mid ventricular cells resulted in a significant decrease in Ito and IKr density. NS3623 increased Ito from 16.4±2.23 to 31.8±4.5pA/pF, and IKr from 0.28±0.06 to 0.47±0.09pA/pF after 2days in culture. AP recordings from 2day cultured cells exhibited a reduced phase 1 repolarization, AP prolongation, and early afterdepolarizations (EADs). NS3623 restored the AP notch and was able to suppress EADs. NS3623 is a dual Ito and IKr activator. Application of this compound to cells with a reduced repolarization reserve resulted in an increase in these currents and a shortening of AP duration, increase in phase 1 repolarization and suppression of EADs. Our results suggest a potential benefit of K+ current activators under conditions of reduced repolarization reserve including heart failure.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2016.03.015