title: Gating of the late Na+ channel in normal and failing human myocardium.
abstract: We previously reported an ultraslow inactivating late Na+ current (INaL) in left ventricular cardiomyocytes (VC) isolated from normal (NVC) and failing (FVC) human hearts. This current could play a role in heart failure-induced repolarization abnormalities. To identify properties of NaCh contributing to INaL, we examined early and late openings in cell-attached patches of HEK293 cells expressing human cardiac NaCh alpha-subunit (alpha-HEK) and in VC of one normal and three failing human hearts. Two types of the late NaCh openings underlay INaL in all three preparations: scattered late (SLO) and bursts (BO). Amplitude analysis revealed that slope conductance for both SLO and BO was the same compared to the main level of early openings (EO) in both VC (21 vs 22.7pS, NVC; 22.7 vs 22.6pS, FVC) and alpha-HEK (23.2 vs 23pS), respectively. Analysis of SLO latencies revealed voltage-independent ultraslow inactivation in all preparations with tendency to be slower in FVC compared to NCV. EO and SLO render one open voltage-independent state (tau approximately 0.4ms) for NVC and FVC. One open (voltage-dependent) and two closed states (one voltage-dependent and another voltage-independent) were found in BO of both specimens. Burst duration tend to be longer in FVC ( approximately 50ms) than in NVC ( approximately 30ms). In FVC we found both modes SLO and BO at membrane potential of -10mV that is attribute for take-off voltages (from -18 to -2mV) for early afterdepolarizations (EAD's) in FVC. In conclusions, we found a novel gating mode SLO that manifest slow (hundreds of ms), voltage-independent inactivation in both NVC and FVC. We were unable to reliably demonstrate any differences in the properties of the late NaCh in failing vs a normal human heart. Accordingly, the late current appears to be generated by a single population of channels in normal and failing human ventricular myocardium. Both SLO and BO could be implicated in EADs in HF.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan 48202-2689, USA. aundrov1@hfhs.org
authors.forename: Albertas I
authors.initials: AI
authors.lastname: Undrovinas
authors.forename: Victor A
authors.initials: VA
authors.lastname: Maltsev
authors.forename: John W
authors.initials: JW
authors.lastname: Kyle
authors.forename: Norman
authors.initials: N
authors.lastname: Silverman
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000200:Action Potentials; D002478:Cells, Cultured / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D017136:Ion Transport; D007668:Kidney; D007700:Kinetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*; D013997:Time Factors
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D011993:Recombinant Fusion Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D012964:Sodium