Extracellular sodium dependence of the conduction velocity-calcium relationship: evidence of ephaptic self-attenuation

Extracellular sodium dependence of the conduction velocity-calcium relationship: evidence of ephaptic self-attenuation. George, S. A., Bonakdar, M., Zeitz, M., Davalos, R. V., Smyth, J. W., & Poelzing, S. Am J Physiol Heart Circ Physiol, 310(9):H1129-39, 2016. 1522-1539 George, Sharon A Bonakdar, Mohammad Zeitz, Michael Davalos, Rafael V Smyth, James W Poelzing, Steven R01 HL102298/HL/NHLBI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States 2016/03/06 Am J Physiol Heart Circ Physiol. 2016 May 1;310(9):H1129-39. doi: 10.1152/ajpheart.00857.2015. Epub 2016 Mar 4.
doi abstract bibtex

Our laboratory previously demonstrated that perfusate sodium and potassium concentrations can modulate cardiac conduction velocity (CV) consistent with theoretical predictions of ephaptic coupling (EpC). EpC depends on the ionic currents and intercellular separation in sodium channel rich intercalated disk microdomains like the perinexus. We suggested that perinexal width (WP) correlates with changes in extracellular calcium ([Ca(2+)]o). Here, we test the hypothesis that increasing [Ca(2+)]o reduces WP and increases CV. Mathematical models of EpC also predict that reducing WP can reduce sodium driving force and CV by self-attenuation. Therefore, we further hypothesized that reducing WP and extracellular sodium ([Na(+)]o) will reduce CV consistent with ephaptic self-attenuation. Transmission electron microscopy revealed that increasing [Ca(2+)]o (1 to 3.4 mM) significantly decreased WP Optically mapping wild-type (WT) (100% Cx43) mouse hearts demonstrated that increasing [Ca(2+)]o increases transverse CV during normonatremia (147.3 mM), but slows transverse CV during hyponatremia (120 mM). Additionally, CV in heterozygous (∼50% Cx43) hearts was more sensitive to changes in [Ca(2+)]o relative to WT during normonatremia. During hyponatremia, CV slowed in both WT and heterozygous hearts to the same extent. Importantly, neither [Ca(2+)]o nor [Na(+)]o altered Cx43 expression or phosphorylation determined by Western blotting, or gap junctional resistance determined by electrical impedance spectroscopy. Narrowing WP, by increasing [Ca(2+)]o, increases CV consistent with enhanced EpC between myocytes. Interestingly, during hyponatremia, reducing WP slowed CV, consistent with theoretical predictions of ephaptic self-attenuation. This study suggests that serum ion concentrations may be an important determinant of cardiac disease expression.

@article{RN177,
   author = {George, S. A. and Bonakdar, M. and Zeitz, M. and Davalos, R. V. and Smyth, J. W. and Poelzing, S.},
   title = {Extracellular sodium dependence of the conduction velocity-calcium relationship: evidence of ephaptic self-attenuation},
   journal = {Am J Physiol Heart Circ Physiol},
   volume = {310},
   number = {9},
   pages = {H1129-39},
   note = {1522-1539
George, Sharon A
Bonakdar, Mohammad
Zeitz, Michael
Davalos, Rafael V
Smyth, James W
Poelzing, Steven
R01 HL102298/HL/NHLBI NIH HHS/United States
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
United States
2016/03/06
Am J Physiol Heart Circ Physiol. 2016 May 1;310(9):H1129-39. doi: 10.1152/ajpheart.00857.2015. Epub 2016 Mar 4.},
   abstract = {Our laboratory previously demonstrated that perfusate sodium and potassium concentrations can modulate cardiac conduction velocity (CV) consistent with theoretical predictions of ephaptic coupling (EpC). EpC depends on the ionic currents and intercellular separation in sodium channel rich intercalated disk microdomains like the perinexus. We suggested that perinexal width (WP) correlates with changes in extracellular calcium ([Ca(2+)]o). Here, we test the hypothesis that increasing [Ca(2+)]o reduces WP and increases CV. Mathematical models of EpC also predict that reducing WP can reduce sodium driving force and CV by self-attenuation. Therefore, we further hypothesized that reducing WP and extracellular sodium ([Na(+)]o) will reduce CV consistent with ephaptic self-attenuation. Transmission electron microscopy revealed that increasing [Ca(2+)]o (1 to 3.4 mM) significantly decreased WP Optically mapping wild-type (WT) (100% Cx43) mouse hearts demonstrated that increasing [Ca(2+)]o increases transverse CV during normonatremia (147.3 mM), but slows transverse CV during hyponatremia (120 mM). Additionally, CV in heterozygous (∼50% Cx43) hearts was more sensitive to changes in [Ca(2+)]o relative to WT during normonatremia. During hyponatremia, CV slowed in both WT and heterozygous hearts to the same extent. Importantly, neither [Ca(2+)]o nor [Na(+)]o altered Cx43 expression or phosphorylation determined by Western blotting, or gap junctional resistance determined by electrical impedance spectroscopy. Narrowing WP, by increasing [Ca(2+)]o, increases CV consistent with enhanced EpC between myocytes. Interestingly, during hyponatremia, reducing WP slowed CV, consistent with theoretical predictions of ephaptic self-attenuation. This study suggests that serum ion concentrations may be an important determinant of cardiac disease expression.},
   keywords = {*Action Potentials
Animals
Calcium/*metabolism
*Calcium Signaling
*Cell Communication
Computer Simulation
Connexin 43/deficiency/genetics
Dielectric Spectroscopy
Electric Impedance
Gap Junctions/metabolism
Genotype
Hyponatremia/blood/physiopathology
Isolated Heart Preparation
Kinetics
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron, Transmission
*Models, Cardiovascular
Myocytes, Cardiac/*metabolism/ultrastructure
Phenotype
Sodium/*metabolism
Voltage-Sensitive Dye Imaging
calcium
conduction
ephaptic coupling
ion concentration
sodium},
   ISSN = {0363-6135 (Print)
0363-6135},
   DOI = {10.1152/ajpheart.00857.2015},
   year = {2016},
   type = {Journal Article}
}

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