Transgenic upregulation of IK1 in the mouse heart is proarrhythmic.
The role of the cardiac current Ik1 in arrhythmogenesis remains highly controversal. To gain further insights into the mechanisms of IK1 involvement in cardiac excitability, we studied the susceptibility of transgenic mice with altered IK1 to arrhythmia during various pharmacological and physiological challenges. Arrhythmogenesis was studied in transgenic mice expressing either dominant negative Kir2.1-AAA or wild type Kir2.1 subunits in the heart, models of IK1 suppression (AAA-TG) and up-regulation (WT-TG), respectively. Under normal conditions, both anesthetized wild type (WT) and AAA-TG mice did not display any spontaneous arrhythmias. In contrast,WT-TG mice displayed numerous arrhythmias of various types. In isolated hearts, the threshold concentration for halothane-induced ventricular tachycardias (VT) was increased to 167% [corrected] in the AAA-TG and decreased to 54% [corrected] in WT-TG hearts when compared to WT hearts. The number of PVCs induced by AV node ablation combined with hypokalemia was reduced in AAA-TG hearts and increased in WT-TG mice. After AV node ablation AAA-TG hearts were more tolerant, and WT-TG less tolerant to isoproterenol- induced arrhythmias than WT hearts. Analysis of monophasic action potentials in isolated hearts shows a significant reduction in the dispersion of action potential repolarization in mice with suppressed IK1. The data strongly support the hypothesis that in the mouse heart upregulation of IK1 is proarrhythmic, and that under certain conditions IK1 blockade in cardiac myocytes may be a potentially useful antiarrhythmic strategy.
Piao
Lin
L
Department of Molecular & Integrative Physiology, University of Michigan, Room 7812, Medical Science II, 1150 W Medical Center Drive, Ann Arbor MI 48109, USA.
Li
Jingdong
J
McLerie
Meredith
M
Lopatin
Anatoli N
AN
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology* / Q000628:therapy; D002316:Cardiotonic Agents / Q000494:pharmacology; D017115:Catheter Ablation; D004562:Electrocardiography; D005260:Female; D006221:Halothane / Q000494:pharmacology; D007008:Hypokalemia / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; D007545:Isoproterenol; D006221:Halothane