Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs.

Abstract

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 mug/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.

• Authors: James K Hennan, Robert E Swillo, Gwen A Morgan, James C Keith Jr, Robert G Schaub, Robert P Smith, Hal S Feldman, Ketil Haugan, Joel Kantrowitz, Phil J Wang, Aqel Abu-Qare, John Butera, Bjarne D Larsen, David L Crandall
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 317 Issue 1 Pg. 236-43 (Apr 2006) ISSN: 0022-3565 [Print] United States
• PMID: 16344331 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Oligopeptides
• rotigaptide

Topics

• Animals
• Anti-Arrhythmia Agents (adverse effects, pharmacokinetics, therapeutic use)
• Dogs
• Gap Junctions (ultrastructure)
• Hemodynamics (drug effects)
• Microscopy, Electron, Transmission
• Myocardial Infarction (drug therapy, etiology, pathology, physiopathology)
• Myocardial Reperfusion Injury (complications, pathology, physiopathology)
• Myocardium (ultrastructure)
• Oligopeptides (adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome
• Ventricular Premature Complexes (etiology, pathology, physiopathology, prevention & control)