Proceedings of The Physiological Society

Kings College London (2005) J Physiol 565P, PC163


Disparate conduction slowing in guinea pig left and right atrium during gap junction uncoupling

Dhillon, Paramdeep Singh; Gray, Rosaire ; Stavrou, Bridgitte ; Hussain, Wajid ; Fry, Chris ; Peters, Nicholas ;

1. Cardiac Electrophysiology, Imperial College, London, United Kingdom. 2. Institute of Urology, University College, London, United Kingdom.

Gap-junction (GJ) channels, composed of connexin (Cx) proteins, are important determinants of action potential (AP) propagation in the heart. Chamber-specific patterns of Cx expression contribute to regional differences in conduction velocity (CV). The effects of Cx reduction on CV are poorly understood; Cx-knockout studies produce conflicting results and attempts at pharmacological manipulation have been hindered by effects on active membrane properties, which also determine CV. Carbenoxolone, a Cx43-uncoupler, has recently been shown to reduce rabbit ventricular and atrial CVs without altering membrane ionic currents (de Groot et al, 2003). CV reductions were of a similar magnitude despite distinct patterns of Cx40 and 43 expression and different control CVs. Our study aimed to explore how CV slowed during GJ uncoupling of right and left guinea pig atrium. Male guinea pigs were killed by cervical dislocation. Trabeculae from left and right atrial appendages were superfused with Tyrode's solution (5%COnull2null, 24mM NaHCOnull3null, pH 7.4, 37oC). Preparations were stimulated with an extracellular bipolar electrode to initiate conducted APs at 1Hz. CV, AP upstroke velocity (Vnullmaxnull) and the time constant of the AP foot (τnullapnull) were measured before, during and after superfusion with 20μM carbenoxolone. Intracellular resistivity (Rnullinull) was calculated from the 1-D cable equation. Data are mean ± S.D. Differences between means (p<0.05) were examined by Student's t-test. Control CVs were similar in the left and right atrium (78.8±4.29 vs.77.6±6.42 cm.s-1, respectively n=5), However τnullapnull was smaller and Vnullmaxnull greater in left compared to right atrium (0.20±0.03 vs. 0.33±0.12ms, n=5 p=0.04 and 107.7±5 vs. 75.4±13.5 V.s-1, n=5 p=0.003). Calculated Rnullinull, assuming a cell radius of 4.6μm and 4.2μm for left and right atrium respectively (Wang et al, 1999), was significantly greater in the left atrium (192±46 vs. 116±35Ω.cm, n=5 p=0.02). Carbenoxolone slowed CV more in the left atrium (21.3±7.9 vs. 11.8±5.0 % reduction respectively, n=5 p=0.05). In left atrium, Vnullmaxnull increased from 101.3±5.6 to 138.4±6.3 V.s-1 (n=4, p=0.01), AP amplitude (APA) increased from 105.2±1.6 to 118.6±3.3 mV (n=4 p=0.004) and Rnullinull increased from 192±46 to 342±103 Ω.cm (n=5, p=0.04). Values of right atrial Vnullmaxnull , APA and Rnullinull were not statistically altered by carbenoxolone. The effects on CV were fully reversible on washout, but Vnullmaxnull remained elevated in left atrial preparations. AP duration (75% repolarisation), τnullapnull,and membrane potential were unaffected by carbenoxolone. Thus carbenoxolone slowed atrial conduction by increasing Ri with a greater effect on the left compared to right atrial appendage.

Where applicable, experiments conform with Society ethical requirements