Attenuation of IK,slow1 and IK,slow2 in Kv1/Kv2DN mice prolongs APD and QT intervals but does not suppress spontaneous or inducible arrhythmias
Open Access
- 1 January 2004
- journal article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 286 (1) , H368-H374
- https://doi.org/10.1152/ajpheart.00303.2003
Abstract
Overexpression of a truncated Kv1.1 or Kv2.1 channel polypeptide in the heart (Kv1DN or Kv2DN) resulted in mice with a prolonged action potential duration (APD) due to marked attenuation of rapidly activating, slowly inactivating K+ current ( I K,slow1) or slowly inactivating outward K+ current ( I K,slow2) in ventricular myocytes. ECG monitoring, optical mapping, and programmed electrical stimulation of Kv1DN mice revealed spontaneous and inducible reentrant ventricular tachycardia due to spatial dispersion of repolarization and refractoriness. Recently, we demonstrated upregulation of I K,slow2 in apical cardiomyocytes derived from Kv1DN mice. We therefore hypothesized that the selective upregulation of Kv2.1-encoded currents underlies the apex-to-base dispersion of repolarization and the reentrant arrhythmias. To test this hypothesis, the Kv1DN line was crossbred with the Kv2DN line to produce Kv1/Kv2DN lines. Whole cell voltage-clamp recordings from left ventricular cells of Kv1/Kv2DN confirmed that the 4-aminopyridine- and tetraethylammonium-sensitive components of I K,slow were eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, and Kv2DN cells. Telemetric ECG recordings revealed prolongation of the corrected QT in Kv1/Kv2DN compared with Kv1DN and Kv2DN mice. However, attenuation of Kv2.1-encoded currents in Kv1DN mice did not suppress the arrhythmias. Thus, the elimination of I K,slow2 prolongs APD and the QT intervals, but does not have an antiarrhythmic effect.Keywords
This publication has 16 references indexed in Scilit:
- A Defect in the Kv Channel-Interacting Protein 2 (KChIP2) Gene Leads to a Complete Loss of Ito and Confers Susceptibility to Ventricular TachycardiaCell, 2001
- Characterization of mice with a combined suppression ofI to and I K,slowAmerican Journal of Physiology-Heart and Circulatory Physiology, 2001
- Inducible polymorphic ventricular tachyarrhythmias in a transgenic mouse model with a long Q-T phenotype.American Journal of Physiology-Heart and Circulatory Physiology, 2000
- Enhanced Dispersion of Repolarization and Refractoriness in Transgenic Mouse Hearts Promotes Reentrant Ventricular TachycardiaCirculation Research, 2000
- Replacement by Homologous Recombination of the minK Gene With lacZ Reveals Restriction of minK Expression to the Mouse Cardiac Conduction SystemCirculation Research, 1999
- Inhibition of Cardiac Delayed Rectifier K + Current by Overexpression of the Long-QT Syndrome HERG G628S Mutation in Transgenic MiceCirculation Research, 1998
- Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 α SubunitCirculation Research, 1998
- Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channelProceedings of the National Academy of Sciences, 1998
- A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndromeCell, 1995
- Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patchesPflügers Archiv - European Journal of Physiology, 1981