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J Pharmacol Exp Ther ; 329(3): 1127-33, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19252062

ABSTRACT

Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Our objective was to determine whether GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], a small dipeptide gap junction modifier, can improve conduction and ultimately prevent AF/AFL. In rat atrial strips subjected to metabolic stress, GAP-134 prevented significantly conduction velocity slowing at 10 nM compared with vehicle (p < 0.01). In the canine sterile pericarditis model, conduction time (CT; n = 5), atrial effective refractory period (AERP; n = 3), and AF/AFL duration/inducibility (n = 16) were measured 2 to 3 days postoperatively in conscious dogs. CT was significantly faster after GAP-134 infusion (average plasma concentration, 250 nM) at cycle lengths of 300 ms (66.2 +/- 1.0 versus 62.0 +/- 1.0 ms; p < 0.001) and 200 ms (64.4 +/- 0.9 versus 61.0 +/- 1.3 ms; p < 0.001). No significant changes in AERP were noted after GAP-134 infusion. The mean number of AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7 +/- 0.6 versus 1.6 +/- 0.8; p < 0.01), with total AF/AFL burden being decreased from 12,280 to 6063 s. Western blot experiments showed no change in connexin 43 expression. At concentrations exceeding those described in the AF/AFL experiments, GAP-134 had no effect on heart rate, blood pressure, or any electrocardiogram parameters. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential antiarrhythmic efficacy.


Subject(s)
Atrial Fibrillation/drug therapy , Atrial Flutter/drug therapy , Benzamides/therapeutic use , Dipeptides/therapeutic use , Gap Junctions/drug effects , Heart Conduction System/drug effects , Pericarditis/drug therapy , Proline/analogs & derivatives , Animals , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/physiopathology , Atrial Flutter/physiopathology , Benzamides/pharmacology , Connexin 43/metabolism , Dipeptides/adverse effects , Dipeptides/pharmacology , Disease Models, Animal , Dogs , Electric Conductivity , Female , Gap Junctions/physiology , Heart Atria/drug effects , Heart Atria/metabolism , Heart Atria/physiopathology , Heart Conduction System/physiology , Male , Molecular Structure , Oligopeptides/pharmacology , Oligopeptides/therapeutic use , Pericarditis/physiopathology , Postoperative Complications/drug therapy , Postoperative Complications/physiopathology , Proline/pharmacology , Proline/therapeutic use , Rats , Rats, Sprague-Dawley , Refractory Period, Electrophysiological/drug effects
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