Treatment with the gap junction modifier rotigaptide (ZP123) reduces infarct size in rats with chronic myocardial infarction.
Treatment with non-selective drugs (eg, long-chain alcohols, halothane) that reduce gap junction intercellular communication (GJIC) is associated with reduced infarct size after myocardial infarction (MI). Therefore, it has been suggested that gap junction intercellular communication stimulating compounds may increase infarct size. The antiarrhythmic peptide analogue rotigaptide (ZP123) increases cardiac gap junction intercellular communication and the purpose of the present study was to examine the effects of rotigaptide treatment on infarct size. Myocardial infarction was induced in male rats by ligation of the left anterior descending artery (LAD). Rats (n = 156) were treated with rotigaptide at three dose levels or vehicle from the onset of ischemia and for 3 weeks following LAD occlusion. Infarct size was determined using histomorphometry after 3 weeks treatment. Rotigaptide treatment producing steady state plasma levels of 0.8 +/- 0.1, 5.5 +/- 0.5, and 86 +/- 8 nmol/L had no effect on mortality, but reduced infarct size to 90 +/- 10% (P = 0.41), 67 +/- 7% (P = 0.005), and 82 +/- 7% (P = 0.13), respectively relative to vehicle-treated myocardial infarction rats (100 +/- 12%). In contrast to what was predicted, our data demonstrates that rotigaptide treatment was associated with a significant infarct size reduction. We conclude that whereas treatment with non-selective inhibitors of gap junction intercellular communication cause a reduction in infarct size, this information cannot be extrapolated to the effects of compounds that selectively increase gap junction intercellular communication.
Zealand Pharma A/S, Department of Pharmacology, Glostrup, Denmark.
Ketil
K
Haugan
Niels
N
Marcussen
Anne Louise
AL
Kjølbye
Morten Schak
MS
Nielsen
James K
JK
Hennan
Jørgen Søberg
JS
Petersen
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D017629:Gap Junctions / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D009842:Oligopeptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D009842:Oligopeptides; C477643:rotigaptide