Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene

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 (CV_T) 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 CV_T in WT and HZ hearts, with the greatest effect in HZ hearts. Increasing [Na⁺]_o increased CV_T only in HZ hearts. Increasing [K⁺]_o slowed CV_T 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.