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| Content Provider | PubMed Central |
|---|---|
| Author | Chevalier, Morgan Bogdan, Amuzescu Gawali, Vaibhavkumar Todt, Hannes Knott, Thomas Scheel, Olaf Abriel, Hugues |
| Copyright Year | 2014 |
| Abstract | The cardiac late Na+ current is generated by a small fraction of voltage-dependent Na+ channels that undergo a conformational change to a burst-gating mode, with repeated openings and closures during the action potential (AP) plateau. Its magnitude can be augmented by inactivation-defective mutations, myocardial ischemia, or prolonged exposure to chemical compounds leading to drug-induced (di)-long QT syndrome, and results in an increased susceptibility to cardiac arrhythmias. Using CytoPatch™ 2 automated patch-clamp equipment, we performed whole-cell recordings in HEK293 cells stably expressing human Nav1.5, and measured the late Na+ component as average current over the last 100 ms of 300 ms depolarizing pulses to -10 mV from a holding potential of -100 mV, with a repetition frequency of 0.33 Hz. Averaged values in different steady-state experimental conditions were further corrected by the subtraction of current average during the application of tetrodotoxin (TTX) 30 μM. We show that ranolazine at 10 and 30 μM in 3 min applications reduced the late Na+ current to 75.0 ± 2.7% (mean ± SEM,n = 17) and 58.4 ± 3.5% (n = 18) of initial levels, respectively, while a 5 min application of veratridine 1 μM resulted in a reversible current increase to 269.1 ± 16.1% (n = 28) of initial values. Using fluctuation analysis, we observed that ranolazine 30 μM decreased mean open probabilityp from 0.6 to 0.38 without modifying the number of active channelsn, while veratridine 1 μM increasedn 2.5-fold without changingp. In human iPSC-derived cardiomyocytes, veratridine 1 μM reversibly increased APD90 2.12 ± 0.41-fold (mean ± SEM,n = 6). This effect is attributable to inactivation removal in Nav1.5 channels, since significant inhibitory effects on hERG current were detected at higher concentrations in hERG-expressing HEK293 cells, with a 28.9 ± 6.0% inhibition (mean ± SD,n = 10) with 50 μM veratridine. |
| Related Links | http://dx.doi.org/10.12688/f1000research.5544.1 |
| Starting Page | 245 |
| File Format | |
| ISSN | 20461402 |
| e-ISSN | 20461402 |
| Journal | F1000Research |
| Volume Number | 3 |
| Language | English |
| Publisher | F1000Research |
| Publisher Date | 2014-10-01 |
| Access Restriction | Open |
| Rights Holder | F1000Research |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Microbiology Medicine Biochemistry, Genetics and Molecular Biology Pharmacology, Toxicology and Pharmaceutics |
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