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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

Cardiovascular and Metabolic Disease Research Wyeth Research, Collegeville, Pennsylvania, hennanj{at}wyeth.com

Robert E. Swillo, MS

Cardiovascular and Metabolic Disease Research Wyeth Research, Collegeville, Pennsylvania

Gwen A. Morgan

Cardiovascular and Metabolic Disease Research Wyeth Research, Collegeville, Pennsylvania

Eric I. Rossman, PhD

Cardiovascular and Metabolic Disease Research Wyeth Research, Collegeville, Pennsylvania

Joel Kantrowitz, PhD

Drug Safety and Metabolism Wyeth Research, Collegeville, Pennsylvania

John Butera, PhD

Chemical and Screening Sciences Wyeth Research Wyeth Research, Collegeville, Pennsylvania,

Jorgen S. Petersen, MD, PhD

Zealand Pharma A/S Glostrup, Denmark

Stephen J. Gardell, PhD

Cardiovascular and Metabolic Disease Research Wyeth Research, Collegeville, Pennsylvania,

George P. Vlasuk, PhD

Cardiovascular and Metabolic Disease Research Wyeth Research, Collegeville, Pennsylvania,

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 µg/kg bolus + 0.19 µg/kg per hour infusion; 2.5 µg/kg + 1.9 µg/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.

Key Words: gap junction • arrhythmia • ischemia • infarct size • ventricular tachycardia

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 14, No. 3, 207-214 (2009)
DOI: 10.1177/1074248409340779


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