title: Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure.
abstract: We elucidate the role of late Na+ current (INaL) for diastolic intracellular Ca2+ (DCa) accumulation in chronic heart failure (HF). HF was induced in 19 dogs by multiple coronary artery microembolizations; 6 normal dogs served as control. Ca2+ transients were recorded in field-paced (0.25 or 1.5 Hz) fluo-4-loaded ventricular myocytes (VM). INaL and action potentials were recorded by patch-clamp. Failing VM, but not normal VM, exhibited (1) prolonged action potentials and Ca2+ transients at 0.25 Hz, (2) substantial DCa accumulation at 1.5 Hz, and (3) spontaneous Ca2+ releases, which occurred after 1.5 Hz stimulation trains in ~31% cases. Selective INaL blocker ranolazine (10 microM) or the prototypical Na+ channel blocker tetrodotoxin (2 microM) reversibly improved function of failing VM. The DCa accumulation and the beneficial effect of INaL blockade were reproduced in silico using an excitation-contraction coupling model. We conclude that INaL contributes to diastolic Ca2+ accumulation and spontaneous Ca2+ release in HF.
authors.affiliation: Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202-2689, USA.
authors.forename: Nidas A
authors.initials: NA
authors.lastname: Undrovinas
authors.forename: Victor A
authors.initials: VA
authors.lastname: Maltsev
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Albertas
authors.initials: A
authors.lastname: Undrovinas
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003198:Computer Simulation; D004285:Dogs; D006333:Heart Failure / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D000069458:Ranolazine; D012964:Sodium / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D010879:Piperazines; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D012964:Sodium; D000069458:Ranolazine; D002118:Calcium