title: The gap junction modifier, GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], improves conduction and reduces atrial fibrillation/flutter in the canine sterile pericarditis model.
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.
authors.affiliation: Cardiovascular and Metabolic Disease, Wyeth Research, Collegeville, PA 19426, USA.
authors.forename: Eric I
authors.initials: EI
authors.lastname: Rossman
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Morgan
authors.forename: Robert E
authors.initials: RE
authors.lastname: Swillo
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: John
authors.initials: J
authors.lastname: Butera
authors.forename: Matthew
authors.initials: M
authors.lastname: Gruver
authors.forename: Joel
authors.initials: J
authors.lastname: Kantrowitz
authors.forename: Hal S
authors.initials: HS
authors.lastname: Feldman
authors.forename: Jørgen S
authors.initials: JS
authors.lastname: Petersen
authors.forename: Ketil
authors.initials: K
authors.lastname: Haugan
authors.forename: James K
authors.initials: JK
authors.lastname: Hennan
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D001282:Atrial Flutter / Q000188:drug therapy* / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D018031:Connexin 43 / Q000378:metabolism; D004151:Dipeptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004553:Electric Conductivity; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D010493:Pericarditis / Q000188:drug therapy* / Q000503:physiopathology; D011183:Postoperative Complications / Q000188:drug therapy / Q000503:physiopathology; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
chemical_list: C541429:1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D018031:Connexin 43; D004151:Dipeptides; D009842:Oligopeptides; D011392:Proline; C477643:rotigaptide