Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction

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Abstract
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...