title: Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes.
abstract: The slowly inactivating or late Na+ current, INa-L, can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major working hypothesis is that the Na+ influx corresponding to INa-L significantly increases intracellular Na+, [Na+]i; and the resulting reduction in the electrochemical driving force for Na+ reduces and (may reverse) Na+/Ca2+ exchange. These changes increase intracellular Ca2+, [Ca2+]i; which may further enhance INa-L due to calmodulin-dependent phosphorylation of the Na+ channels. This paper is based on mathematical simulations using the O'Hara et al (2011) model of baseline or healthy human ventricular action potential waveforms(s) and its [Ca2+]i homeostasis mechanisms. Somewhat surprisingly, our results reveal only very small changes (≤ 1.5 mM) in [Na+]i even when INa-L is increased 5-fold and steady-state stimulation rate is approximately 2 times the normal human heart rate (i.e. 2 Hz). Previous work done using well-established models of the rabbit and human ventricular action potential in heart failure settings also reported little or no change in [Na+]i when INa-L was increased. Based on our simulations, the major short-term effect of markedly augmenting INa-L is a significant prolongation of the action potential and an associated increase in the likelihood of reactivation of the L-type Ca2+ current, ICa-L. Furthermore, this action potential prolongation does not contribute to [Na+]i increase.
authors.affiliation: Centro de Investigación e Innovación en Bioingeniería, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Karen
authors.initials: K
authors.lastname: Cardona
authors.affiliation: Centro de Investigación e Innovación en Bioingeniería, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Beatriz
authors.identifier: http://orcid.org/0000-0001-9166-6112
authors.initials: B
authors.lastname: Trenor
authors.affiliation: Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Giles
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D012964:Sodium; D002118:Calcium