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CARDIOVASCULAR

Rotigaptide (ZP123) Prevents Spontaneous Ventricular Arrhythmias and Reduces Infarct Size During Myocardial Ischemia/Reperfusion Injury in Open-Chest Dogs

Cardiovascular and Metabolic Disease Research (J.K.H., R.E.S., G.A.M., J.C.K., R.G.S., D.L.C.), Vaccines Research (R.P.S.), Drug Safety and Metabolism (H.S.F., J.K., P.J.W., A.A.-Q.), Chemical and Screening Sciences (J.B.), Wyeth Research, Collegeville, Pennsylvania; and Zealand Pharma A/S, Glostrup, Denmark (K.H., B.D.L.)

The antiarrhythmic and cardioprotective effect of increasing gap junction intercellular communication during ischemia/reperfusion injury has not been studied. The antiarrhythmic peptide rotigaptide (previously ZP123), which maintains gap junction intercellular communication, was tested in dogs subjected to a 60-min coronary artery occlusion and 4 h of reperfusion. Rotigaptide was administered i.v. 10 min before reperfusion as a bolus + i.v. infusion at doses of 1 ng/kg bolus + 10 ng/kg/h infusion (n = 6), 10 ng/kg bolus + 100 ng/kg/h infusion (n = 5), 100 ng/kg bolus + 1000 ng/kg/h infusion (n = 8), 1000 ng/kg bolus + 10 µg/kg/h infusion (n = 6), and vehicle control (n = 5). Premature ventricular complexes (PVCs) were quantified during reperfusion. A series of four or more consecutive PVCs was defined as ventricular tachycardia (VT). The total incidence of VT was reduced significantly with the two highest doses of rotigaptide (20.3 ± 10.9 and 4.3 ± 4.1 events; p < 0.05) compared with controls (48.7 ± 6.0). Total PVCs were reduced significantly from 25.1 ± 4.2% in control animals to 11.0 ± 4.4 and 1.7 ± 1.3% after the two highest doses of rotigaptide. Infarct size, expressed as a percentage of the left ventricle, was reduced significantly from 13.2 ± 1.9 in controls to 7.1 ± 1.0 (p < 0.05) at the highest dose of rotigaptide. Ultrastructural evaluation revealed no differences in myocardial injury in the infarct area, area at risk, border zone, or normal zone in vehicle and rotigaptide-treated animals. However, rotigaptide did increase the presence of gap junctions in the area at risk (p = 0.022, Fisher's exact test). Rotigaptide had no effect on heart rate, blood pressure, heart rate-corrected QT interval, or left ventricular end-diastolic pressure. In conclusion, these results demonstrate that rotigaptide is a potent antiarrhythmic compound with cardioprotective effects and desirable safety.

Address correspondence to: Dr. James K. Hennan, Wyeth Research, P.O. Box 42528, Philadelphia, PA 19101. E-mail: hennanj{at}wyeth.com

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