title: Late Sodium Current in Human Atrial Cardiomyocytes from Patients in Sinus Rhythm and Atrial Fibrillation.
abstract: Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (ΔKPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 μM) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ΔKPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 μM) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, TU Dresden, Dresden, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Poulet
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, TU Dresden, Dresden, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.affiliation: Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.affiliation: Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.affiliation: Clinic for Cardiac Surgery, Heart Center Dresden, Dresden, Germanymailto.
authors.forename: Klaus
authors.initials: K
authors.lastname: Matschke
authors.affiliation: Clinic for Cardiac Surgery, Heart Center Dresden, Dresden, Germanymailto.
authors.forename: Michael
authors.initials: M
authors.lastname: Knaut
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, TU Dresden, Dresden, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D000818:Animals; D001146:Arrhythmia, Sinus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001281:Atrial Fibrillation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D000069458:Ranolazine / Q000494:pharmacology; D015222:Sodium Channels; D013696:Temperature; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D021122:Protein Subunits; D015222:Sodium Channels; D013779:Tetrodotoxin; D000069458:Ranolazine