Roles of subcellular Na+ channel distributions in the mechanism of cardiac conduction.

The gap junction and voltage-gated Na(+) channel play an important role in the action potential propagation. The purpose of this study was to elucidate the roles of subcellular Na(+) channel distribution in action potential propagation. To achieve this, we constructed the myocardial strand model, which can calculate the current via intercellular cleft (electric-field mechanism) together with gap-junctional current (gap-junctional mechanism). We conducted simulations of action potential propagation in a myofiber model where cardiomyocytes were electrically coupled with gap junctions alone or with both the gap junctions and the electric field mechanism. Then we found that the action potential propagation was greatly affected by the subcellular distribution of Na(+) channels in the presence of the electric field mechanism. The presence of Na(+) channels in the lateral membrane was important to ensure the stability of propagation under conditions of reduced gap-junctional coupling. In the poorly coupled tissue with sufficient Na(+) channels in the lateral membrane, the slowing of action potential propagation resulted from the periodic and intermittent dysfunction of the electric field mechanism. The changes in the subcellular Na(+) channel distribution might be in part responsible for the homeostatic excitation propagation in the diseased heart.

[1]  Jamie I Vandenberg,et al.  Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M Delmar,et al.  Characterization of Conduction in the Ventricles of Normal and Heterozygous Cx43 Knockout Mice Using Optical Mapping , 1999, Journal of cardiovascular electrophysiology.

[3]  Ruben Coronel,et al.  Conduction slowing by the gap junctional uncoupler carbenoxolone. , 2003, Cardiovascular research.

[4]  Yoram Rudy,et al.  A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue. , 1987 .

[5]  Jeffrey E. Saffitz,et al.  Electrical Propagation in Synthetic Ventricular Myocyte Strands From Germline Connexin43 Knockout Mice , 2004, Circulation research.

[6]  Yoram Rudy,et al.  Localization of Sodium Channels in Intercalated Disks Modulates Cardiac Conduction , 2002, Circulation research.

[7]  W. Catterall,et al.  An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Candido Cabo,et al.  Remodeling in Cells From Different Regions of the Reentrant Circuit During Ventricular Tachycardia , 2005, Circulation.

[9]  B. Katz.  Nerve, Muscle and Synapse , 1966 .

[10]  Y Rudy,et al.  Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. , 1997, Circulation research.

[11]  R. W. Joyner,et al.  Effects of the Discrete Pattern of Electrical Coupling on Propagation through an Electrical Syncytium , 1982, Circulation research.

[12]  C. Orchard,et al.  No Apparent Requirement for Neuronal Sodium Channels in Excitation-Contraction Coupling in Rat Ventricular Myocytes , 2006, Circulation research.

[13]  Shingo Murakami,et al.  Physiological modulation of voltage-dependent inactivation in the cardiac muscle L-type calcium channel: a modelling study. , 2008, Progress in biophysics and molecular biology.

[14]  Mark E. Anderson,et al.  Voltage-gated Nav channel targeting in the heart requires an ankyrin-G–dependent cellular pathway , 2008, The Journal of cell biology.

[15]  J. D. de Bakker,et al.  Impaired Impulse Propagation in Scn5a-Knockout Mice: Combined Contribution of Excitability, Connexin Expression, and Tissue Architecture in Relation to Aging , 2005, Circulation.

[16]  A. McDonough,et al.  Subcellular distribution of sodium pump isoform subunits in mammalian cardiac myocytes. , 1996, The American journal of physiology.

[17]  W. Shimizu,et al.  The electrophysiologic mechanism of ST-segment elevation in Brugada syndrome. , 2002, Journal of the American College of Cardiology.

[18]  N. Sperelakis.  Heart physiology and pathophysiology , 2001 .

[19]  Carlo Napolitano,et al.  Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Steven Poelzing,et al.  Altered connexin43 expression produces arrhythmia substrate in heart failure. , 2004, American journal of physiology. Heart and circulatory physiology.

[21]  D. Geselowitz,et al.  The Discontinuous Nature of Propagation in Normal Canine Cardiac Muscle: Evidence for Recurrent Discontinuities of Intracellular Resistance that Affect the Membrane Currents , 1981, Circulation research.

[22]  D. Bers,et al.  Surface:volume relationship in cardiac myocytes studied with confocal microscopy and membrane capacitance measurements: species-dependence and developmental effects. , 1996, Biophysical journal.

[23]  M. Yeager,et al.  Structure of cardiac gap junction intercellular channels. , 1998, Journal of structural biology.

[24]  R. Kieval,et al.  Immunofluorescence localization of the Na-Ca exchanger in heart cells. , 1992, The American journal of physiology.

[25]  R C Barr,et al.  Electrophysiological effects of remodeling cardiac gap junctions and cell size: experimental and model studies of normal cardiac growth. , 2000, Circulation research.

[26]  D. Kass,et al.  Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts. , 2005, Cardiovascular research.

[27]  Andrew L Wit,et al.  Cell Coupling Between Ventricular Myocyte Pairs From Connexin43-Deficient Murine Hearts , 2003, Circulation research.

[28]  J. Makielski,et al.  CHAPTER 6 – Excitability and Impulse Propagation , 2001 .

[29]  N. Severs.  Cardiac muscle cell interaction: from microanatomy to the molecular make-up of the gap junction. , 1995, Histology and histopathology.

[30]  J. E. Mann,et al.  Evaluation of electric field changes in the cleft between excitable cells. , 1977, Journal of theoretical biology.

[31]  J. Brugada,et al.  Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. , 1992, Journal of the American College of Cardiology.

[32]  C. Luo,et al.  A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. , 1994, Circulation research.

[33]  Michael D. Schneider,et al.  Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 , 2001, Circulation research.

[34]  Y Rudy,et al.  Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study. , 2000, Biophysical journal.

[35]  K. Sunagawa,et al.  Transmural heterogeneity of the action potential configuration in the feline left ventricle. , 2003, Circulation journal : official journal of the Japanese Circulation Society.

[36]  Yoichiro Mori,et al.  Ephaptic conduction in a cardiac strand model with 3D electrodiffusion , 2008, Proceedings of the National Academy of Sciences.

[37]  K. Sunagawa,et al.  Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil. , 2005, Journal of the American College of Cardiology.

[38]  C. Green,et al.  Altered patterns of gap junction distribution in ischemic heart disease. An immunohistochemical study of human myocardium using laser scanning confocal microscopy. , 1991, The American journal of pathology.

[39]  A. Moorman,et al.  Heart defects in connexin43-deficient mice. , 1998, Circulation research.

[40]  L. Philipson,et al.  Localization of the Kv1.5 K+ channel protein in explanted cardiac tissue. , 1995, The Journal of clinical investigation.

[41]  N. Sperelakis,et al.  Electric field interactions between closely abutting excitable cells. . , 2002, IEEE engineering in medicine and biology magazine : the quarterly magazine of the Engineering in Medicine & Biology Society.

[42]  J Toyama,et al.  Effects of activation sequence and anisotropic cellular geometry on the repolarization phase of action potential of dog ventricular muscles. , 1987, Circulation.

[43]  S A Cohen,et al.  Immunocytochemical localization of rH1 sodium channel in adult rat heart atria and ventricle. Presence in terminal intercalated disks. , 1996, Circulation.

[44]  A. Kleber,et al.  Electrical uncoupling and increase of extracellular resistance after induction of ischemia in isolated, arterially perfused rabbit papillary muscle. , 1987, Circulation research.

[45]  M. Cooklin,et al.  Changes in cell-to-cell electrical coupling associated with left ventricular hypertrophy. , 1997, Circulation research.

[46]  Yoshihisa Kurachi,et al.  In silico risk assessment for drug-induction of cardiac arrhythmia. , 2008, Progress in biophysics and molecular biology.

[47]  Y Rudy,et al.  Mechanistic Insights Into Very Slow Conduction in Branching Cardiac Tissue: A Model Study , 2001, Circulation research.

[48]  J. Spear,et al.  Gap junctional conductance in ventricular myocyte pairs isolated from postischemic rabbit myocardium. , 1992, Circulation research.

[49]  J E Saffitz,et al.  Distribution and Three‐Dimensional Structure of Intercellular Junctions in Canine Myocardium , 1989, Circulation research.

[50]  R. Weingart,et al.  Electrical properties of gap junction channels in guinea-pig ventricular cell pairs revealed by exposure to heptanol , 1989, Pflügers Archiv.

[51]  J. Nerbonne,et al.  Differential expression of voltage-gated K+ channel subunits in adult rat heart. Relation to functional K+ channels? , 1995, Circulation Research.