Victor A Maltsev1, Albertas I Undrovinas. 1. Henry Ford Heart and Vascular Institute, Henry Ford Hospital, Cardiovascular Research Bldg. Room 4015, 2799 West Grand Boulevard Detroit, MI 48202-2689, USA.
Abstract
OBJECTIVE: We reported an ultraslow late Na+ current (INaL) in ventricular cardiomyocytes of human hearts. INaL has been implicated in regulation of action potential duration in normal hearts and repolarization abnormalities in failing hearts. We have also identified sodium channel (NaCh) gating modes including bursts (BM) and late scattered openings (LSM) that together comprise INaL; however, the contribution of these gating modes to Na+ current (INa) remains unknown. In the present study, the late NaCh activity was recorded, analyzed, and modeled for heterologously expressed NaCh, Nav1.5, and for the native NaCh of ventricular mid-myocardial cardiomyocytes from normal and failing hearts. METHODS AND RESULTS: We found that LSM gating was significantly slower in failing compared to normal myocytes and Nav1.5 (tau=474+/-10 vs. 299+/-9, and 229+/-12 ms, m+/-SEM; P<0.05, n=5-6). Total burst length of BM decreased with depolarization and was larger in failing compared to normal myocytes and Nav1.5. A complete INa decay was then numerically approximated as composed of NaCh populations operating in three gating modes described by separate Markov kinetic schemes: transient mode (TM), LSM, and BM. The populations of NaCh operating in each gating mode were estimated as 79.8% for TM, 20% for LSM, and 0.2% for BM, yielding an apparent four-exponential INa decay at -30 mV (maximum INa) (tau i approximately 0.4, 4, 50, and 500 ms). Whole-cell recordings confirmed the existence of all four predicted components. The model also predicted voltage and temperature dependence of INaL as well as INaL increase and slower decay in failing hearts and acceleration by amiodarone. CONCLUSIONS: The early phase of Na+ current decay (<40 ms) involves all three NaCh gating modes, the intermediate phase (from 40 to 300 ms) is produced by BM+LSM, although the contribution of BM decreases with depolarization, and ultra-late decay (>300 ms) is determined solely by LSM. The concept of multi-mode composition for INaL provides a new rationale for INaL modulation by factors such as voltage, temperature, pharmacological agents, and pathological conditions.
OBJECTIVE: We reported an ultraslow late Na+ current (INaL) in ventricular cardiomyocytes of human hearts. INaL has been implicated in regulation of action potential duration in normal hearts and repolarization abnormalities in failing hearts. We have also identified sodium channel (NaCh) gating modes including bursts (BM) and late scattered openings (LSM) that together comprise INaL; however, the contribution of these gating modes to Na+ current (INa) remains unknown. In the present study, the late NaCh activity was recorded, analyzed, and modeled for heterologously expressed NaCh, Nav1.5, and for the native NaCh of ventricular mid-myocardial cardiomyocytes from normal and failing hearts. METHODS AND RESULTS: We found that LSM gating was significantly slower in failing compared to normal myocytes and Nav1.5 (tau=474+/-10 vs. 299+/-9, and 229+/-12 ms, m+/-SEM; P<0.05, n=5-6). Total burst length of BM decreased with depolarization and was larger in failing compared to normal myocytes and Nav1.5. A complete INa decay was then numerically approximated as composed of NaCh populations operating in three gating modes described by separate Markov kinetic schemes: transient mode (TM), LSM, and BM. The populations of NaCh operating in each gating mode were estimated as 79.8% for TM, 20% for LSM, and 0.2% for BM, yielding an apparent four-exponential INa decay at -30 mV (maximum INa) (tau i approximately 0.4, 4, 50, and 500 ms). Whole-cell recordings confirmed the existence of all four predicted components. The model also predicted voltage and temperature dependence of INaL as well as INaL increase and slower decay in failing hearts and acceleration by amiodarone. CONCLUSIONS: The early phase of Na+ current decay (<40 ms) involves all three NaCh gating modes, the intermediate phase (from 40 to 300 ms) is produced by BM+LSM, although the contribution of BM decreases with depolarization, and ultra-late decay (>300 ms) is determined solely by LSM. The concept of multi-mode composition for INaL provides a new rationale for INaL modulation by factors such as voltage, temperature, pharmacological agents, and pathological conditions.
Authors: Albertas I Undrovinas; Victor A Maltsev; John W Kyle; Norman Silverman; Hani N Sabbah Journal: J Mol Cell Cardiol Date: 2002-11 Impact factor: 5.000
Authors: A C Zygmunt; G T Eddlestone; G P Thomas; V V Nesterenko; C Antzelevitch Journal: Am J Physiol Heart Circ Physiol Date: 2001-08 Impact factor: 4.733
Authors: Ye Chen-Izu; Robin M Shaw; Geoffrey S Pitt; Vladimir Yarov-Yarovoy; Jon T Sack; Hugues Abriel; Richard W Aldrich; Luiz Belardinelli; Mark B Cannell; William A Catterall; Walter J Chazin; Nipavan Chiamvimonvat; Isabelle Deschenes; Eleonora Grandi; Thomas J Hund; Leighton T Izu; Lars S Maier; Victor A Maltsev; Celine Marionneau; Peter J Mohler; Sridharan Rajamani; Randall L Rasmusson; Eric A Sobie; Colleen E Clancy; Donald M Bers Journal: J Physiol Date: 2015-03-15 Impact factor: 5.182
Authors: J-F Desaphy; A Dipalma; T Costanza; C Bruno; G Lentini; C Franchini; Al George; D Conte Camerino Journal: Br J Pharmacol Date: 2010-07 Impact factor: 8.739
Authors: Victor A Maltsev; Vitaliy Reznikov; Nidas A Undrovinas; Hani N Sabbah; Albertas Undrovinas Journal: Am J Physiol Heart Circ Physiol Date: 2008-01-18 Impact factor: 4.733