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.
Ursell PC, Gardner PI, Albala A., Fenoglio JJ Jr, Wit ALStructural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. Circ Res. 1985;56(3):436-451.
2.
Dillon SM, Allessie MA, Ursell PC, Wit ALInfluences of anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. Circ Res. 1988;63(1):182-206.
3.
De Groot JR, Coronel R.Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis . Cardiovasc Res.2004;62(2):323-334.
4.
Yao JA, Hussain W., Patel P., Peters NS, Boyden PA, Wit ALRemodeling of gap junctional channel function in epicardial border zone of healing canine infarcts. Circ Res. 2003;92(4):437-443.
5.
Xing D., Kjølbye AL, Nielsen MS, et al. ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs. J Cardiovasc Electrophysiol. 2003;14(5):510-520.
6.
Hennan JK, Swillo RE, Morgan GA, et al. Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/ reperfusion injury in open-chest dogs. J Pharmacol Exp Ther. 2006 ;317(1):236-243.
7.
Laurent G., Leong-Poi H., Mangat I., et al. Effects of chronic gap junction conduction-enhancing antiarrhythmic peptide GAP-134 administration on experimental atrial fibrillation in dogs . Circ Arrhythmia Electrophysiol. 2009;2:171-178.
8.
Rossman EI, Liu K., Morgan GA, et al. Effects of the gap junction modifier, GAP-134, on conduction and atrial fibrillation/flutter inducibility and maintenance in dogs. Revised, resubmitted to J Pharmacol Exp Ther. 2009;329(3):1127-33.
9.
Butera JA, Larsen BD, Hennan JK, et al. Discovery of (2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine2-carboxylic acid hydrochloride (GAP-134)13, an Orally Active Small Molecule Gap-Junction Modifier for the Treatment of Atrial Fibrillation. J. Med Chem. 2009; 26;52(4):908-11.
10.
Black SC, Driscoll EM, Lucchesi BREffect of ramiprilat or captopril on myocardial infarct size: assessment in canine models of ischemia alone and ischemia with reperfusion. Pharmacology. 1998;57(1):35-46.
11.
Walker MJ, Curtis MJ, Hearse DJ, et al. The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion. Cardiovasc Res. 1988;22(7):447-455.
12.
Heymann MA, Payne BD, Hoffman JI, Rudolph AMBlood flow measurements with radionuclide-labeled particles. Prog Cardiovasc Dis. 1977;20(1):55-79.
13.
Black SC, Rodger IWMethods for studying experimental myocardial ischemic and reperfusion injury . J Pharmacol Toxicol Methods. 1996 ;35(4):179-190.
14.
Kléber AG, Riegger CB, Janse MJElectrical uncoupling and increase of extracellular resistance after induction of ischemia in isolated, arterially perfused rabbit papillary muscle. Circ Res. 1987;61(2):271-279.
15.
Smith WT 4th , Fleet WF , Johnson TA, Engle CL, Cascio WEThe 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. Circulation. 1995;92(10):3051-3060.
16.
Yao JA, Hussain W., Patel P., Peters NS, Boyden PA, Wit ALRemodeling of gap junctional channel function in epicardial border zone of healing canine infarcts. Circ Res. 2003;92(4):437-43.
17.
Cinca J., Warren M., Carreño A., et al. Changes in myocardial electrical impedance induced by coronary artery occlusion in pigs with and without preconditioning: correlation with local ST-segment potential and ventricular arrhythmias. Circulation . 1997;96(9):3079-3086.
18.
Papp R., Gönczi M., Kovács M., Seprényi G., Végh A.Gap junctional uncoupling plays a trigger role in the antiarrhythmic effect of ischaemic preconditioning. Cardiovasc Res.2007;74(3):396-405.
19.
Beardslee MA , Lerner DL, Tadros PN, et al. Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res. 2000;87(8):656-662.
20.
Lampe PD, Lau AFThe effects of connexin phosphorylation on gap junctional communication . Int J Biochem Cell Biol. 2004;36(7):1171-1186.
21.
Axelsen LN, Stahlhut M., Mohammed S., et al. Identification of ischemia-regulated phosphorylation sites in connexin43: A possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123). J Mol Cell Cardiol. 2006;40(6):790-798.
22.
Schulz R., Gres P., Skyschally A., et al. Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J. 2003;17(10):1355-1357.
23.
García-Dorado D., Rodríguez-Sinovas A., Ruiz-Meana M.Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion. Cardiovasc Res.2004;61(3):386-401.
24.
Matchkov VV , Rahman A., Peng H., Nilsson H., Aalkjaer C.Junctional and nonjunctional effects of heptanol and glycyrrhetinic acid derivates in rat mesenteric small arteries. Br J Pharmacol. 2004;142(6):961-972.
25.
Li G., Whittaker P., Yao M., Kloner RA, Przyklenk K.The gap junction uncoupler heptanol abrogates infarct size reduction with preconditioning in mouse hearts. Cardiovasc Pathol. 2002;11(3):158-165.
26.
Burmeister WE, Reynolds RDComparison of infarct size produced by coronary artery occlusion in purebred beagle and mixed-breed dogs. Can J Physiol Pharmacol. 1983;61(7):672-675.
27.
Jugdutt BIDifference in the relation between infarct and occluded bed in pentobarbital-anesthetized and conscious dogs. Can J Physiol Pharmacol. 1986;64(3): 254-262.
