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Ca2+-activated Cl− current is antiarrhythmic by reducing both spatial and temporal heterogeneity of cardiac repolarization
| Content Provider | Scilit |
|---|---|
| Author | Hegyi, Bence Horváth, Balázs Váczi, Krisztina Gönczi, Mónika Kistamás, Kornél Ruzsnavszky, Ferenc Veress, Roland Izu, Leighton T. Chen-Izu, Ye Bányász, Tamás Csernoch, László Nánási, Péter P. Szentandrássy, Norbert |
| Copyright Year | 2017 |
| Description | Journal: Journal of Molecular and Cellular Cardiology The role of $Ca^{2+}$-activated $Cl^{−}$ current $(I_{Cl(Ca)}$) in cardiac arrhythmias is still controversial. It can generate delayed afterdepolarizations in $Ca^{2+}$-overloaded cells while in other studies incidence of early afterdepolarization (EAD) was reduced by $I_{Cl(Ca)}$. Therefore our goal was to examine the role of $I_{Cl(Ca)}$ in spatial and temporal heterogeneity of cardiac repolarization and EAD formation. Experiments were performed on isolated canine cardiomyocytes originating from various regions of the left ventricle; subepicardial, midmyocardial and subendocardial cells, as well as apical and basal cells of the midmyocardium. $I_{Cl(Ca)}$ was blocked by 0.5mmol/L 9-anthracene carboxylic acid (9-AC). Action potential (AP) changes were tested with sharp microelectrode recording. Whole-cell 9-AC-sensitive current was measured with either square pulse voltage-clamp or AP voltage-clamp (APVC). Protein expression of TMEM16A and Bestrophin-3, ion channel proteins mediating $I_{Cl(Ca)}$, was detected by Western blot. 9-AC reduced phase-1 repolarization in every tested cell. 9-AC also increased AP duration in a reverse rate-dependent manner in all cell types except for subepicardial cells. Neither $I_{Cl(Ca)}$ density recorded with square pulses nor the normalized expressions of TMEM16A and Bestrophin-3 proteins differed significantly among the examined groups of cells. The early outward component of $I_{Cl(Ca)}$ was significantly larger in subepicardial than in subendocardial cells in APVC setting. Applying a typical subepicardial AP as a command pulse resulted in a significantly larger early outward component in both subepicardial and subendocardial cells, compared to experiments when a typical subendocardial AP was applied. Inhibiting $I_{Cl(Ca)}$ by 9-AC generated EADs at low stimulation rates and their incidence increased upon beta-adrenergic stimulation. 9-AC increased the short-term variability of repolarization also. We suggest a protective role for $I_{Cl(Ca)}$ against risk of arrhythmias by reducing spatial and temporal heterogeneity of cardiac repolarization and EAD formation. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995131/pdf http://www.jmcc-online.com/article/S0022282817301256/pdf |
| Ending Page | 37 |
| Page Count | 11 |
| Starting Page | 27 |
| ISSN | 00222828 |
| e-ISSN | 10958584 |
| DOI | 10.1016/j.yjmcc.2017.06.014 |
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume Number | 109 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2017-06-28 |
| Access Restriction | Open |
| Subject Keyword | Journal: Journal of Molecular and Cellular Cardiology Ca2+-activated Cl− Current Spatial Heterogeneity of Repolarization Short-term Variability of Repolarization Early Afterdepolarization 9-anthracene Carboxylic Acid Action Potential Duration Action Potential Duration At 90% of Repolarization Action Potential Voltage-clamp Pore Forming Subunit of L-type Ca2+ Channel |
| Content Type | Text |
| Resource Type | Article |
| Subject | Molecular Biology Cardiology and Cardiovascular Medicine |
