title: Heart Rate and Extracellular Sodium and Potassium Modulation of Gap Junction Mediated Conduction in Guinea Pigs.
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).
  
  
  OBJECTIVE
  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.
authors: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State UniversityBlacksburg, VA, USA; Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Virginia Polytechnic Institute and State UniversityRoanoke, VA, USA.
authors: Michael
authors: M
authors: Entz
authors: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State UniversityBlacksburg, VA, USA; Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Virginia Polytechnic Institute and State UniversityRoanoke, VA, USA.
authors: Sharon A
authors: SA
authors: George
authors: Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Virginia Polytechnic Institute and State University Roanoke, VA, USA.
authors: Michael J
authors: MJ
authors: Zeitz
authors: Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Virginia Polytechnic Institute and State UniversityRoanoke, VA, USA; Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State UniversityBlacksburg, VA, USA.
authors: Tristan
authors: T
authors: Raisch
authors: Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Virginia Polytechnic Institute and State UniversityRoanoke, VA, USA; Department of Biological Sciences, College of Science, Virginia Polytechnic Institute and State UniversityBlacksburg, VA, USA.
authors: James W
authors: JW
authors: Smyth
authors: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State UniversityBlacksburg, VA, USA; Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Virginia Polytechnic Institute and State UniversityRoanoke, VA, USA; Department of Biological Sciences, College of Science, Virginia Polytechnic Institute and State UniversityBlacksburg, VA, USA.
authors: Steven
authors: S
authors: Poelzing
keywords: cardiac conduction; electrophysiology; ephaptic coupling; gap junction