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. METHODS AND 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.

[1]  W. Cascio,et al.  The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Experimental Cardiology Group, University of North Carolina. , 1995, Circulation.

[2]  J. Soler‐Soler,et al.  Gap junction uncoupler heptanol prevents cell-to-cell progression of hypercontracture and limits necrosis during myocardial reperfusion. , 1997, Circulation.

[3]  G. Zampighi,et al.  Structural characteristics of gap junctions. I. Channel number in coupled and uncoupled conditions , 1988, The Journal of cell biology.

[4]  Y. Takagishi,et al.  Remodeling of gap junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonary hypertension. , 2000, Circulation research.

[5]  K. A. Yamada,et al.  Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. , 2000, Circulation.

[6]  R Wilders,et al.  Gap junctions in cardiovascular disease. , 2000, Circulation research.

[7]  M. Takahira,et al.  Two types of K+ currents modulated by arachidonic acid in bovine corneal epithelial cells. , 2001, Investigative ophthalmology & visual science.

[8]  M. Mirabet,et al.  Persistence of gap junction communication during myocardial ischemia. , 2001, American journal of physiology. Heart and circulatory physiology.

[9]  M. Janse,et al.  Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. , 1989, Physiological reviews.

[10]  M. Rook,et al.  Mechanism of heptanol-induced uncoupling of cardiac gap junctions: a perforated patch-clamp study. , 1992, The American journal of physiology.

[11]  A. Kleber,et al.  Slow conduction in cardiac tissue, I: effects of a reduction of excitability versus a reduction of electrical coupling on microconduction. , 1998, Circulation research.

[12]  J. Soler‐Soler,et al.  Propagation of cardiomyocyte hypercontracture by passage of Na(+) through gap junctions. , 1999, Circulation research.

[13]  Bertram Pitt,et al.  Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction , 1996, The Lancet.

[14]  Michael D. Schneider,et al.  Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 , 2001, Circulation research.

[15]  R Plonsey,et al.  In vivo estimation of cardiac transmembrane current. , 1993, Circulation research.

[16]  A. Wilde,et al.  Changes in conduction velocity during acute ischemia in ventricular myocardium of the isolated porcine heart. , 1986, Circulation.

[17]  J. Burt,et al.  Uncoupling of cardiac cells by fatty acids: structure-activity relationships. , 1991, The American journal of physiology.

[18]  E. V. Van Bockstaele,et al.  Functional Coupling between Neurons and Glia , 2000, The Journal of Neuroscience.

[19]  C. Luo,et al.  A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. , 1994, Circulation research.

[20]  J. Tytgat How to isolate cardiac myocytes. , 1994, Cardiovascular research.

[21]  Action potential conduction between guinea pig ventricular cells can be modulated by calcium current. , 1992, The American journal of physiology.

[22]  J. Eledjam,et al.  Effects of halothane and enflurane on ventricular conduction, refractoriness, and wavelength: a concentration-response study in isolated hearts. , 1999, Anesthesiology.

[23]  N S Peters,et al.  Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. , 1997, Circulation.

[24]  P. Poole‐Wilson,et al.  Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. , 1993, Circulation.

[25]  R Weingart,et al.  Action potential transfer in cell pairs isolated from adult rat and guinea pig ventricles. , 1988, Circulation research.

[26]  W. Rogers,et al.  Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. , 1989, The New England journal of medicine.

[27]  J J Heger,et al.  Sudden cardiac death. , 1998, Circulation.

[28]  B. Egan,et al.  Carbenoxolone damages endothelium and enhances vasoconstrictor action in aortic rings. , 1996, Hypertension.

[29]  T. Shimada,et al.  Modulation of voltage-dependent Ca channel current by arachidonic acid and other long-chain fatty acids in rabbit intestinal smooth muscle , 1992, The Journal of general physiology.

[30]  R Wilders,et al.  Action potential conduction between a ventricular cell model and an isolated ventricular cell. , 1996, Biophysical journal.

[31]  Yin Zhang,et al.  Evidence that disruption of connexon particle arrangements in gap junction plaques is associated with inhibition of gap junctional communication by a glycyrrhetinic acid derivative. , 1996, Experimental cell research.

[32]  M. Szente,et al.  Involvement of electrical coupling in the in vivo ictal epileptiform activity induced by 4-aminopyridine in the neocortex , 2002, Neuroscience.

[33]  T. Opthof,et al.  Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling. , 2001, Cardiovascular research.

[34]  R. Coronel,et al.  Laplacian Electrograms and the Interpretation of Complex Ventricular Activation Patterns During Ventricular Fibrillation , 2000, Journal of cardiovascular electrophysiology.

[35]  R. Ruch,et al.  Gap‐junction disassembly and connexin 43 dephosphorylation induced by 18β‐glycyrrhetinic acid , 1996, Molecular carcinogenesis.

[36]  Y Rudy,et al.  Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. , 1997, Circulation research.

[37]  M. Sheets,et al.  Mechanisms of extracellular divalent and trivalent cation block of the sodium current in canine cardiac Purkinje cells. , 1992, The Journal of physiology.

[38]  M. Spach,et al.  Relating Extracellular Potentials and Their Derivatives to Anisotropic Propagation at a Microscopic Level in Human Cardiac Muscle: Evidence for Electrical Uncoupling of Side‐to‐Side Fiber Connections with Increasing Age , 1986, Circulation research.

[39]  M Kamermans,et al.  Hemichannel-Mediated Inhibition in the Outer Retina , 2001, Science.

[40]  M. Allessie,et al.  Altered Pattern of Connexin40 Distribution in Persistent Atrial Fibrillation in the Goat , 1998, Journal of cardiovascular electrophysiology.

[41]  A. Zygmunt,et al.  Properties of the calcium-activated chloride current in heart , 1992, The Journal of general physiology.

[42]  A. V. van Ginneken,et al.  Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias. , 2001, Cardiovascular research.

[43]  M. Weir,et al.  The Cardiac Arrhythmia Suppression Trial Investigators: Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression After Myocardial Infarction. , 1990 .