Conduction slowing by the gap junctional uncoupler carbenoxolone

doi:10.1016/j.cardiores.2003.07.004

Cardiovascular Research 2003 60(2):288-297; doi:10.1016/j.cardiores.2003.07.004
© 2003 by European Society of Cardiology

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Conduction slowing by the gap junctional uncoupler carbenoxolone

Joris R. de Groot^a^,1, Thijs Veenstra^b^,1, Arie O. Verkerk^a^,b, Ronald Wilders^b, Jeroen P.P. Smits^a, Francien J.G. Wilms-Schopman^c, Rob F. Wiegerinck^a, Jan Bourier^b, Charly N.W. Belterman^a, Ruben Coronel^a^,d^,1 and E.Etienne Verheijck^*^,b^,1

^aAcademic Medical Center, Task Force Heart Failure and Ageing, Experimental and Molecular Cardiology Group, Department of Experimental Cardiology, Amsterdam, The Netherlands
^bAcademic Medical Center, Task Force Heart Failure and Ageing, Department of Physiology, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
^cInteruniversity Cardiology Institute the Netherlands, Utrecht, The Netherlands
^dHeart Lung Center Utrecht, Department of Cardiology, University Medical Center Utrecht, The Netherlands

*Corresponding author. Tel.: +31-20-5664670; fax: +31-20-6919319. Email address: e.verheijck{at}amc.uva.nl

Background: Cellular electrical coupling is essential for normalpropagation of the cardiac action potential, whereas reducedelectrical coupling is associated with arrhythmias. Known cellularuncoupling agents have severe side effects on membrane ioniccurrents. We investigated the effect of carbenoxolone on cellularelectrical coupling, membrane ionic currents, and atrial andventricular conduction. Methods and Results: In isolated rabbitleft ventricular and right atrial myocytes, carbenoxolone (50µmol/l) had no effect on action potential characteristics.Calcium, potassium, and sodium currents remained unchanged.Dual current clamp experiments on poorly coupled cell pairsrevealed a 21±3% decrease in coupling conductance bycarbenoxolone (mean±S.E.M., n = 4, p<0.05). High-densityactivation mapping was performed in intact rabbit atrium andventricle during Langendorff perfusion of the heart. The amplitudeof the Laplacian of the electrograms, a measure of couplingcurrent in intact hearts, decreased from 1.45±0.66 to0.75±0.51 µA/mm³ (mean±SD, n = 32, p<0.05)after 15 min of carbenoxolone. Carbenoxolone reversibly decreasedlongitudinal and transversal conduction velocity from 66±15to 49±16 cm/s and from 50±14 to 35±15 cm/sin ventricle, respectively (mean±SD, n = 5, both p<0.05).In atrium, longitudinal and transversal conduction velocitydecreased from 80±29 to 60±16 cm/s and from 49±10to 38±10 cm/s (mean±SD, n = 8, both p<0.05).Conclusions: Carbenoxolone-induced uncoupling causes atrialand ventricular conduction slowing without affecting cardiacmembrane currents. Activation delay is larger in poorly coupledcells.

KEYWORDS Experimental; Heart; Organism; Cellular; Electrophysiology; Arrhythmias; Antiarrhythmic agents; Cellular communication; Conduction; Membrane potential

¹ Both authors contributed equally.

Time for primary review 20 days

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