title: GAP-134 ([2S,4R]-1-[2-aminoacetyl]4-benzamidopyrrolidine-2-carboxylic acid) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs.
abstract: The antiarrhythmic dipeptide, GAP-134, ([2S,4R]-1[2-aminoacetyl]-4-benzamido-pyrrolidine-2-carboxylic acid) was evaluated in canine ischemia/reperfusion model. In dogs subjected to 60-minute ischemia and 4-hour reperfusion, GAP-134 was administered 10 minutes before reperfusion as a bolus + intravenous (IV) infusion. The doses administered were 0.25 microg/kg bolus + 0.19 microg/kg per hour infusion; 2.5 microg/kg + 1.9 microg/kg per hour; 25 mg/kg + 19 mg/kg per hour; 75 mg/kg + 57 mg/kg per hour. Ventricular ectopy was quantified during reperfusion, including premature ventricular contractions (PVC) and ventricular tachycardia (VT). Total incidence of VT was reduced significantly with the 2 highest doses of GAP-134 (1.7 + 0.8; 2.2 + 1.4 events; P < .05) compared to controls (23.0 + 6.1). Total PVCs were reduced significantly from 11.1 + 1.6% in control animals to 2.0% + 0.7% and 1.8% + 0.8% after the 2 highest doses of GAP-134. Infarct size, expressed as percentage of left ventricle, was reduced significantly from 19.0% + 3.5% in controls to 7.9% + 1.5% and 7.1% + 0.8% (P < .05) at the 2 highest doses of GAP-134. GAP-134 is an effective antiarrhythmic agent with potential to reduce ischemia/reperfusion injury.
authors.affiliation: Cardiovascular and Metabolic Disease Research, Collegeville, Pennsylvania, USA. hennanj@wyeth.com
authors.forename: James K
authors.initials: JK
authors.lastname: Hennan
authors.forename: Robert E
authors.initials: RE
authors.lastname: Swillo
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Morgan
authors.forename: Eric I
authors.initials: EI
authors.lastname: Rossman
authors.forename: Joel
authors.initials: J
authors.lastname: Kantrowitz
authors.forename: John
authors.initials: J
authors.lastname: Butera
authors.forename: Jorgen S
authors.initials: JS
authors.lastname: Petersen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D018879:Ventricular Premature Complexes / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: C541429:1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D011392:Proline