Conduction slowing by the gap junctional uncoupler carbenoxolone.
BACKGROUND
Cellular electrical coupling is essential for normal propagation of the cardiac action potential, whereas reduced electrical coupling is associated with arrhythmias. Known cellular uncoupling agents have severe side effects on membrane ionic currents. We investigated the effect of carbenoxolone on cellular electrical coupling, membrane ionic currents, and atrial and ventricular conduction.


RESULTS
In isolated rabbit left ventricular and right atrial myocytes, carbenoxolone (50 micromol/l) had no effect on action potential characteristics. Calcium, potassium, and sodium currents remained unchanged. Dual current clamp experiments on poorly coupled cell pairs revealed a 21+/-3% decrease in coupling conductance by carbenoxolone (mean+/-S.E.M., n=4, p<0.05). High-density activation mapping was performed in intact rabbit atrium and ventricle during Langendorff perfusion of the heart. The amplitude of the Laplacian of the electrograms, a measure of coupling current in intact hearts, decreased from 1.45+/-0.66 to 0.75+/-0.51 microA/mm(3) (mean+/-SD, n=32, p<0.05) after 15 min of carbenoxolone. Carbenoxolone reversibly decreased longitudinal and transversal conduction velocity from 66+/-15 to 49+/-16 cm/s and from 50+/-14 to 35+/-15 cm/s in ventricle, respectively (mean+/-SD, n=5, both p<0.05). In atrium, longitudinal and transversal conduction velocity decreased from 80+/-29 to 60+/-16 cm/s and from 49+/-10 to 38+/-10 cm/s (mean+/-SD, n=8, both p<0.05).


CONCLUSIONS
Carbenoxolone-induced uncoupling causes atrial and ventricular conduction slowing without affecting cardiac membrane currents. Activation delay is larger in poorly coupled cells.
de Groot
Joris R
JR
Academic Medical Center, Task Force Heart Failure and Ageing, Department of Experimental Cardiology, Amsterdam, The Netherlands.
Veenstra
Thijs
T
Verkerk
Arie O
AO
Wilders
Ronald
R
Smits
Jeroen P P
JP
Wilms-Schopman
Francien J G
FJ
Wiegerinck
Rob F
RF
Bourier
Jan
J
Belterman
Charly N W
CN
Coronel
Ruben
R
Verheijck
E Etienne
EE
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology*; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D005260:Female; D017629:Gap Junctions / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects*; D007473:Ion Channels / Q000235:genetics; D008297:Male; D010477:Perfusion; D011817:Rabbits; D014475:Uncoupling Agents / Q000494:pharmacology*
D007473:Ion Channels; D014475:Uncoupling Agents; D002229:Carbenoxolone