Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist.
This study was undertaken to determine whether the myocardial infarct-sparing effect of ATL-146e, a selective adenosine A(2A) receptor agonist, persists without a rebound effect for at least 48 h and to determine the optimal duration of ATL-146e treatment in anesthetized dogs. Reperfusion injury after myocardial infarction (MI) is associated with inflammation lasting 24-48 h that contributes to ongoing myocyte injury. We previously showed that an ATL-146e infusion, starting just before reperfusion, decreased inflammation and infarct size in dogs examined 2 h after MI without increasing coronary blood flow. In the present study, adult dogs underwent 90 min of left anterior descending coronary artery occlusion. Thirty minutes before reperfusion, ATL-146e (0.01 microg x kg(-1) x min(-1); n = 21) or vehicle (n = 12) was intravenously infused and continued for 2.5 h (protocol 1) or 24 h (protocol 2). At 48 h after reperfusion hearts were excised and assessed for histological risk area and infarct size. Infarct size based on triphenyltetrazolium chloride (TTC) staining as a percentage of risk area was significantly smaller in ATL-146e-treated vs. control dogs (16.7 +/- 3.7% vs. 33.3 +/- 6.2%, P < 0.05; protocol 1). ATL-146e reduced neutrophil accumulation into infarcted myocardium of ATL-146e-treated vs. control dogs (30 +/- 7 vs. 88 +/- 16 cells/high-power field, P < 0.002). ATL-146e infusion for 24 h (protocol 2) conferred no significant additional infarct size reduction compared with 2.5 h of infusion. A 2.5-h ATL-146e infusion initiated 30 min before reperfusion results in marked, persistent (48 h) reduction in infarct size as a percentage of risk area in dogs with a reduction in infarct zone neutrophil infiltration. No significant further benefit was seen with a 24-h infusion.
Patel
Rajan A G
RA
Cardiovascular Division, Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Glover
David K
DK
Broisat
Alexis
A
Kabul
Hasan K
HK
Ruiz
Mirta
M
Goodman
N Craig
NC
Kramer
Christopher M
CM
Meerdink
Denis J
DJ
Linden
Joel
J
Beller
George A
GA
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003131:Combined Modality Therapy; D003326:Coronary Circulation / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D015425:Myocardial Reperfusion; D009205:Myocarditis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D011687:Purines / Q000494:pharmacology*; D013997:Time Factors; D019210:Troponin I / Q000097:blood; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000473:pathology
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D019210:Troponin I; D008790:Metoprolol