title: A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  Ventricular myocytes were isolated and cultured for up to 48 h. 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 ± 4.5 pA/pF, and IKr from 0.28 ± 0.06 to 0.47 ± 0.09 pA/pF after 2 days in culture. AP recordings from 2 day 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Danish National Research Foundation Center for Cardiac Arrhythmias, Department of Veterinary Clinical and Animal Science, University of Copenhagen, DK-1870 Frederiksberg C, Denmark. Electronic address: kirstinec@sund.ku.dk.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.affiliation: Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY 13501, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: Di Diego
authors.affiliation: Zealand Pharma A/S, Smedeland 36, 2600 Glostrup, Denmark.
authors.forename: Rie Schultz
authors.initials: RS
authors.lastname: Hansen
authors.affiliation: Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY 13501, USA.
authors.forename: Shea A
authors.initials: SA
authors.lastname: Nagle
authors.affiliation: Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY 13501, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Treat
authors.affiliation: Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY 13501, USA. Electronic address: jcordeiro@mmrl.edu.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D032342:Muscle Cells / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000166:cytology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C423868:NS 3623; D010671:Phenylurea Compounds; D015221:Potassium Channels; D013777:Tetrazoles
keywords: Action potential repolarization; Cultured cells; Electrophysiology; NS3623; Repolarization reserve