title: Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene.
abstract: Several studies have disagreed on measurements of cardiac conduction velocity (CV) in mice with a heterozygous knockout of the connexin gene Gja1--a mutation that reduces the gap junction (GJ) protein, Connexin43 (Cx43), by 50 %. We noted that perfusate ionic composition varied between studies and hypothesized that extracellular ionic concentration modulates CV dependence on GJs. CV was measured by optically mapping wild-type (WT) and heterozygous null (HZ) hearts serially perfused with solutions previously associated with no change (Solution 1) or CV slowing (Solution 2). In WT hearts, CV was similar for Solutions 1 and 2. However, consistent with the hypothesis, Solution 2 in HZ hearts slowed transverse CV (CVT) relative to Solution 1. Previously, we showed CV slowing in a manner consistent with ephaptic conduction correlated with increased perinexal inter-membrane width (W P) at GJ edges. Thus, W P was measured following perfusion with systematically adjusted [Na(+)]o and [K(+)]o in Solutions 1 and 2. A wider W P was associated with reduced CVT in WT and HZ hearts, with the greatest effect in HZ hearts. Increasing [Na(+)]o increased CVT only in HZ hearts. Increasing [K(+)]o slowed CVT in both WT and HZ hearts with large W P but only in HZ hearts with narrow W P.
  
  
  CONCLUSIONS
  When perinexi are wide, decreasing excitability by modulating [Na(+)]o and [K(+)]o increases CV sensitivity to reduced Cx43. By contrast, CV is less sensitive to Cx43 and ion composition when perinexi are narrow. These results are consistent with cardiac conduction dependence on both GJ and non-GJ (ephaptic) mechanisms.
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.|Center for Heart and Regenerative Medicine, Virginia Tech Carilion Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: George
authors.affiliation: Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Sciuto
authors.affiliation: Department of Mathematics, California Polytechnic State University, San Luis Obispo, CA, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Pathology, University of Utah and ARUP Reference Lab Institute of Research, Salt Lake City, UT, USA.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Salama
authors.affiliation: Department of Mathematics, University of Utah, Salt Lake City, UT, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Keener
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.|Center for Heart and Regenerative Medicine, Virginia Tech Carilion Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gourdie
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA. poelzing@vtc.vt.edu.|Center for Heart and Regenerative Medicine, Virginia Tech Carilion Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA. poelzing@vtc.vt.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Poelzing
mesh_terms: D000818:Animals; D018031:Connexin 43 / Q000235:genetics* / Q000502:physiology*; D017630:Connexins / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006329:Heart Conduction System / Q000378:metabolism* / Q000502:physiology; D006579:Heterozygote; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D011188:Potassium / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D012964:Sodium / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology
chemical_list: D018031:Connexin 43; D017630:Connexins; C543076:GJA1 protein, mouse; D012964:Sodium; D011188:Potassium
keywords: Conduction; Connexin43; Edema; Potassium; Sodium