Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs.
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.
Hennan
James K
JK
Wyeth Research, Philadelphia, PA 19101. hennanj@wyeth.com.
Swillo
Robert E
RE
Morgan
Gwen A
GA
Keith
James C
JC
Schaub
Robert G
RG
Smith
Robert P
RP
Feldman
Hal S
HS
Haugan
Ketil
K
Kantrowitz
Joel
J
Wang
Phil J
PJ
Abu-Qare
Aqel
A
Butera
John
J
Larsen
Bjarne D
BD
Crandall
David L
DL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004285:Dogs; D017629:Gap Junctions / Q000648:ultrastructure; D006439:Hemodynamics / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000648:ultrastructure; D009842:Oligopeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D018879:Ventricular Premature Complexes / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D000889:Anti-Arrhythmia Agents; D009842:Oligopeptides; C477643:rotigaptide