Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist.

Abstract

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.

• Authors: Rajan A G Patel, David K Glover, Alexis Broisat, Hasan K Kabul, Mirta Ruiz, N Craig Goodman, Christopher M Kramer, Denis J Meerdink, Joel Linden, George A Beller
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 297 Issue 2 Pg. H637-42 (Aug 2009) ISSN: 1522-1539 [Electronic] United States
• PMID: 19502555 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ATL 146e
• Adenosine A2 Receptor Agonists
• Anti-Arrhythmia Agents
• Cyclohexanecarboxylic Acids
• Purines
• Troponin I
• Metoprolol

Topics

• Adenosine A2 Receptor Agonists
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Blood Pressure (drug effects)
• Combined Modality Therapy
• Coronary Circulation (drug effects)
• Cyclohexanecarboxylic Acids (pharmacology)
• Dogs
• Female
• Infusions, Intravenous
• Male
• Metoprolol (pharmacology)
• Myocardial Infarction (drug therapy, immunology, pathology)
• Myocardial Reperfusion
• Myocarditis (drug therapy, immunology, pathology)
• Neutrophils (pathology)
• Purines (pharmacology)
• Time Factors
• Troponin I (blood)
• Ventricular Fibrillation (drug therapy, pathology)