Pathophysiological remodeling of mouse cardiac myocytes expressing dominant negative mutant of neuron restrictive silencing factor.
BACKGROUND
It has been previously reported that the transgenic mouse expressing the dominant negative mutant of the neuron restrictive silencing factor (dnNRSF) in the heart died from lethal arrhythmia, so the present study aimed to clarify the electrophysiological alteration of the ventricular myocyte isolated from the dnNRSF mouse.


RESULTS
The action potential (AP) and membrane currents were recorded using the whole-cell patch-clamp method. Intracellular Ca(2+) was measured with Indo-1AM. The AP of dnNRSF myocytes exhibited reduction of resting membrane potential, prolongation of AP duration, and frequent early afterdepolarization (EAD). The EAD was completely inhibited by SEA0400, a specific blocker of the Na(+)-Ca(2+) exchanger (NCX). The most notable alteration of membrane current was a reduction in the inward rectifier K(+) current (I(K1)) density. In addition to re-expression of fetal type cardiac ion channels, a Na(+)-permeable, late inward current was observed in a small population of dnNRSF myocytes. The diastolic intracellular Ca(2+) concentration was also raised in dnNRSF myocytes, and spontaneous Ca(2+) oscillation was induced by β-adrenergic stimulation.


CONCLUSIONS
In dnNRSF myocytes, the "repolarization reserve" of the AP was significantly reduced by specific alterations in membrane currents. Under these conditions, the amplitude of EAD generated by the inward NCX current might be enlarged, thereby increasing the cells' vulnerability to ventricular arrhythmia.
Department of Physiology, Jichi Medical University, Tochigi, Japan. takanom@jichi.ac.jp
Makoto
M
Takano
Hideyuki
H
Kinoshita
Takao
T
Shioya
Masayuki
M
Itoh
Kazuwa
K
Nakao
Koichiro
K
Kuwahara
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010647:Phenyl Ethers / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
D000814:Aniline Compounds; D002118:Calcium; D010647:Phenyl Ethers; D011188:Potassium; D012097:Repressor Proteins; D019831:Sodium-Calcium Exchanger; D000099229:RE1-Silencing Transcription Factor; C430918:SEA 0400