Late Na<sup>+</sup> Current Is [Ca<sup>2+</sup>]<sub>i</sub>-Dependent in Canine Ventricular Myocytes
Enhancement of the late sodium current (I<sub>NaL</sub>) increases arrhythmia propensity in the heart, whereas suppression of the current is antiarrhythmic. In the present study, we investigated I<sub>NaL</sub> in canine ventricular cardiomyocytes under action potential volta...
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oai:doaj.org-article:cedd9842b323421d81788f7c883d48be2021-11-25T18:39:40ZLate Na<sup>+</sup> Current Is [Ca<sup>2+</sup>]<sub>i</sub>-Dependent in Canine Ventricular Myocytes10.3390/ph141111421424-8247https://doaj.org/article/cedd9842b323421d81788f7c883d48be2021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1142https://doaj.org/toc/1424-8247Enhancement of the late sodium current (I<sub>NaL</sub>) increases arrhythmia propensity in the heart, whereas suppression of the current is antiarrhythmic. In the present study, we investigated I<sub>NaL</sub> in canine ventricular cardiomyocytes under action potential voltage-clamp conditions using the selective Na<sup>+</sup> channel inhibitors GS967 and tetrodotoxin. Both 1 µM GS967 and 10 µM tetrodotoxin dissected largely similar inward currents. The amplitude and integral of the GS967-sensitive current was significantly smaller after the reduction of intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) either by superfusion of the cells with 1 µM nisoldipine or by intracellular application of 10 mM BAPTA. Inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII) by KN-93 or the autocamtide-2-related inhibitor peptide similarly reduced the amplitude and integral of I<sub>NaL</sub>. Action potential duration was shortened in a reverse rate-dependent manner and the plateau potential was depressed by GS967. This GS967-induced depression of plateau was reduced by pretreatment of the cells with BAPTA-AM. We conclude that (1) I<sub>NaL</sub> depends on the magnitude of [Ca<sup>2+</sup>]<sub>i</sub> in canine ventricular cells, (2) this [Ca<sup>2+</sup>]<sub>i</sub>-dependence of I<sub>NaL</sub> is mediated by the Ca<sup>2+</sup>-dependent activation of CaMKII, and (3) I<sub>NaL</sub> is augmented by the baseline CaMKII activity.Dénes KissBalázs HorváthTamás HézsőCsaba DienesZsigmond KovácsLeila TopalNorbert SzentandrássyJános AlmássyJános ProrokLászló VirágTamás BányászAndrás VarróPéter P. NánásiJános MagyarMDPI AGarticlelate Na<sup>+</sup> currentcytosolic Ca<sup>2+</sup> concentrationCaMKIIaction potential voltage clampcanine myocytesMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1142, p 1142 (2021) |
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late Na<sup>+</sup> current cytosolic Ca<sup>2+</sup> concentration CaMKII action potential voltage clamp canine myocytes Medicine R Pharmacy and materia medica RS1-441 |
| spellingShingle |
late Na<sup>+</sup> current cytosolic Ca<sup>2+</sup> concentration CaMKII action potential voltage clamp canine myocytes Medicine R Pharmacy and materia medica RS1-441 Dénes Kiss Balázs Horváth Tamás Hézső Csaba Dienes Zsigmond Kovács Leila Topal Norbert Szentandrássy János Almássy János Prorok László Virág Tamás Bányász András Varró Péter P. Nánási János Magyar Late Na<sup>+</sup> Current Is [Ca<sup>2+</sup>]<sub>i</sub>-Dependent in Canine Ventricular Myocytes |
| description |
Enhancement of the late sodium current (I<sub>NaL</sub>) increases arrhythmia propensity in the heart, whereas suppression of the current is antiarrhythmic. In the present study, we investigated I<sub>NaL</sub> in canine ventricular cardiomyocytes under action potential voltage-clamp conditions using the selective Na<sup>+</sup> channel inhibitors GS967 and tetrodotoxin. Both 1 µM GS967 and 10 µM tetrodotoxin dissected largely similar inward currents. The amplitude and integral of the GS967-sensitive current was significantly smaller after the reduction of intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) either by superfusion of the cells with 1 µM nisoldipine or by intracellular application of 10 mM BAPTA. Inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII) by KN-93 or the autocamtide-2-related inhibitor peptide similarly reduced the amplitude and integral of I<sub>NaL</sub>. Action potential duration was shortened in a reverse rate-dependent manner and the plateau potential was depressed by GS967. This GS967-induced depression of plateau was reduced by pretreatment of the cells with BAPTA-AM. We conclude that (1) I<sub>NaL</sub> depends on the magnitude of [Ca<sup>2+</sup>]<sub>i</sub> in canine ventricular cells, (2) this [Ca<sup>2+</sup>]<sub>i</sub>-dependence of I<sub>NaL</sub> is mediated by the Ca<sup>2+</sup>-dependent activation of CaMKII, and (3) I<sub>NaL</sub> is augmented by the baseline CaMKII activity. |
| format |
article |
| author |
Dénes Kiss Balázs Horváth Tamás Hézső Csaba Dienes Zsigmond Kovács Leila Topal Norbert Szentandrássy János Almássy János Prorok László Virág Tamás Bányász András Varró Péter P. Nánási János Magyar |
| author_facet |
Dénes Kiss Balázs Horváth Tamás Hézső Csaba Dienes Zsigmond Kovács Leila Topal Norbert Szentandrássy János Almássy János Prorok László Virág Tamás Bányász András Varró Péter P. Nánási János Magyar |
| author_sort |
Dénes Kiss |
| title |
Late Na<sup>+</sup> Current Is [Ca<sup>2+</sup>]<sub>i</sub>-Dependent in Canine Ventricular Myocytes |
| title_short |
Late Na<sup>+</sup> Current Is [Ca<sup>2+</sup>]<sub>i</sub>-Dependent in Canine Ventricular Myocytes |
| title_full |
Late Na<sup>+</sup> Current Is [Ca<sup>2+</sup>]<sub>i</sub>-Dependent in Canine Ventricular Myocytes |
| title_fullStr |
Late Na<sup>+</sup> Current Is [Ca<sup>2+</sup>]<sub>i</sub>-Dependent in Canine Ventricular Myocytes |
| title_full_unstemmed |
Late Na<sup>+</sup> Current Is [Ca<sup>2+</sup>]<sub>i</sub>-Dependent in Canine Ventricular Myocytes |
| title_sort |
late na<sup>+</sup> current is [ca<sup>2+</sup>]<sub>i</sub>-dependent in canine ventricular myocytes |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/cedd9842b323421d81788f7c883d48be |
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