Pharmacological modulation of cardiac gap junctions to enhance cardiac conduction - Evidence supporting a novel target for antiarrhythmic therapy

Background - Disease-induced alterations of cardiac gap junctions lead to intercellular uncoupling, which is an important mechanism of arrhythmogenesis. Therefore, drugs that selectively open gap junctions potentially offer a novel strategy for antiarrhythmic therapy. Because the peptide ZP123 was found to increase conductance between paired myocytes, we hypothesized that ZP123 would suppress acidosis-induced gap junction closure in the intact heart. Methods and Results - High-resolution optical mapping was used to measure conduction velocity ( CV) and action potential duration from ventricular epicardium of Langendorff-perfused guinea pig hearts at baseline ( pH 7.4) and during 45 minutes of perfusion with acidotic ( pH 6.0) Tyrode's solution with ( n = 8) and without ( control, n = 7) ZP123 (80 nmol/L). Acidosis produced conduction slowing transverse (29.1 +/- 0.1 to 16.8 +/- 0.2 cm/s, P < 0.0001) and longitudinal (47.2 +/- 2.4 to 33.2 +/- 4.8 cm/s, P < 0.0001) to cardiac fibers. Importantly, ZP123 inhibited conduction slowing during acidosis by approximately 60%. The peak effect of ZP123 was achieved after 16 minutes of acidosis, consistent with inhibition of uncoupling. ZP123 did not affect Na+ current in isolated myocytes, additionally affirming that preservation of CV was attributable to the compound's action on gap junctions. ZP123 had no effect on CV in the absence of acidosis, suggesting that drug activity targets gap junctions under metabolic stress. Action potential duration heterogeneity was significantly reduced by ZP123 ( 6.7 +/- 0.8 ms) compared with controls (9.7 +/- 3.1 ms, P < 0.05), presumably by enhancing cell-to-cell coupling. Conclusions - These data suggest that ZP123 significantly attenuates gap junction closure during acidosis. Preservation of intercellular coupling diminished CV slowing and heterogeneous repolarization, eliminating arrhythmogenic substrates.