Abstract
Background: Recent studies suggested that cardiac conduction in murine hearts with narrow perinexi and 50% reduced connexin43 (Cx43) expression is more sensitive to relatively physiological changes of extracellular potassium ([K+]o) and sodium ([Na+]o).Purpose: Determine whether similar [K+]o and [Na+]o changes alter conduction velocity (CV) sensitivity to pharmacologic gap junction (GJ) uncoupling in guinea pigs.Methods: [K+]o and [Na+]o were varied in Langendorff perfused guinea pig ventricles (Solution A: [K+]o = 4.56 and [Na+]o = 153.3 mM. Solution B: [K+]o = 6.95 and [Na+]o = 145.5 mM). Gap junctions were inhibited with carbenoxolone (CBX) (15 and 30 μM). Epicardial CV was quantified by optical mapping. Perinexal width was measured with transmission electron microscopy. Total and phosphorylated Cx43 were evaluated by western blotting.Results: Solution composition did not alter CV under control conditions or with 15μM CBX. Decreasing the basic cycle length (BCL) of pacing from 300 to 160 ms decreased CV uniformly with both solutions. At 30 μM CBX, a change in solution did not alter CV either longitudinally or transversely at BCL = 300 ms. However, reducing BCL to 160 ms caused CV to decrease more in hearts perfused with Solution B than A. Solution composition did not alter perinexal width, nor did it change total or phosphorylated serine 368 Cx43 expression. These data suggest that the solution dependent CV changes were independent of altered perinexal width or GJ coupling. Action potential duration was always shorter in hearts perfused with Solution B than A, independent of pacing rate and/or CBX concentration.Conclusions: Increased heart rate and GJ uncoupling can unmask small CV differences caused by changing [K+]o and [Na+]o. These data suggest that modulating extracellular ionic composition may be a novel anti-arrhythmic target in diseases with abnormal GJ coupling, particularly when heart rate cannot be controlled.
Highlights
Normal cardiac conduction is critical for maintaining efficient pumping of the heart, and abnormal conduction can lead to arrhythmias and sudden cardiac death
Cardiac conduction was quantified from guinea pig ventricles to determine whether increasing [K+]o and decreasing [Na+]o produced similar effects in ex vivo guinea pig as it did in mice hearts (George et al, 2015)
These maps suggest that cardiac conduction under control conditions was similar when hearts were perfused with Solution A or B
Summary
Normal cardiac conduction is critical for maintaining efficient pumping of the heart, and abnormal conduction can lead to arrhythmias and sudden cardiac death. Despite the many proposed mechanisms, the most prominent computational descriptions of EpC are electric field coupling (Rohr et al, 1998; Sperelakis and McConnell, 2002; Lin and Keener, 2010), or a combination of electric field coupling and the alteration of ionic concentrations within restricted extracellular microdomains (Mori et al, 2008; Hand and Peskin, 2010; Lin and Keener, 2010, 2013, 2014). Recent studies suggested that cardiac conduction in murine hearts with narrow perinexi and 50% reduced connexin (Cx43) expression is more sensitive to relatively physiological changes of extracellular potassium ([K+]o) and sodium ([Na+]o). Purpose: Determine whether similar [K+]o and [Na+]o changes alter conduction velocity (CV) sensitivity to pharmacologic gap junction (GJ) uncoupling in guinea pigs
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