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

Sharon A. George, Mohammad Bonakdar, Michael Zeitz, Rafael V. Davalos, James W. Smyth, Steven Poelzing*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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 ([Ca2+]o). Here, we test the hypothesis that increasing [Ca2+]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 [Ca2+]o (1 to 3.4 mM) significantly decreased Wp. Optically mapping wild-type (WT) (100% Cx43) mouse hearts demonstrated that increasing [Ca2+]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 [Ca2+]o relative to WT during normonatremia. During hyponatremia, CV slowed in both WT and heterozygous hearts to the same extent. Importantly, neither [Ca2+]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 [Ca2+]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.

Original languageEnglish (US)
Pages (from-to)H1129-H1139
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number9
StatePublished - May 2016
Externally publishedYes


  • Calcium
  • Conduction
  • Ephaptic coupling
  • Ion concentration
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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