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. Conclusion: 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.
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We would like to thank Dr. Jeffrey E. Saffitz at Harvard Medical School for generously providing us with the Cx43+/− mice and Drs. Robert Price and Jeffrey Davis at the University of South Carolina and Kathy Lowe at Virginia Tech for their assistance with electron microscopy. This work was supported in part by grants from the National Institutes of Health (R01 HL102298-01A1 to SP, R01 HL56728-10A2 to RGG, R01-1DE019355-01 RGG subcontract) and Virginia Tech Carilion Research Institute Medical Research Scholars Award to SG.
Conflict of interest
RGG holds stock in FirstString Research.
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George, S.A., Sciuto, K.J., Lin, J. et al. Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene. Pflugers Arch - Eur J Physiol 467, 2287–2297 (2015). https://doi.org/10.1007/s00424-015-1698-0