Abstract 15443: A Novel Pde7/8 Inhibitor Exhibits Cardio-protective Effects When Given at Reperfusion in Rodent Ischemia-Reperfusion Models
Delayed morbidity and mortality from acute myocardial infarction (AMI) are significant despite improved outcomes with early reperfusion interventions. Strategies to reduce reperfusion injury have the potential to limit infarct size and reduce the risk of progression toward heart failure and death. Phosphodiesterase (PDE) inhibition has been implicated as a cardioprotective approach in ischemia / reperfusion (I/R) injury, and PDE7 inhibition may have a specific anti-inflammatory role in this context. The activity of a novel inhibitor of PDE7 and 8 (PDE78INH) was evaluated in various in vitro and in vivo rodent models of AMI induced by coronary I/R.
Cardiac ischemia was induced by temporary (30-45 min) occlusion of the left coronary artery, followed by reperfusion for up to 24 h. PDE78INH demonstrated a consistent and reproducible reduction in infarct size (>40% at 3 mg/kg i.v.) when administered at the onset of reperfusion in mouse and rat models. By administering the compound at various time points, it was shown that the compound needed to be injected at the onset of reperfusion to achieve maximal cardio-protection. PDE78INH decreased infarct size in a concentration-dependent manner (0.3 - 3 μM) in isolated perfused rat heart, indicating that cardio-protection could be mediated by a direct effect on cardiomyocytes. At doses which reduced infarct size, PDE78INH administered prior to reperfusion did not change arterial pressure or heart rate in rats and mice, indicating that its effect on infarct size was independent of hemodynamic changes. In hypercholesterolemic (ApoE KO) mice subjected to cardiac I/R (40 min/24 h), PDE78INH (3 mg/Kg i.v. 5 min prior to reperfusion) also reduced the infarct size (-28%, p<0.01); the latter results extending the relevance of the new compound’s protective effects to the setting of concomitant vascular disease.
Altogether, these results identify PDE78INH as a putative novel approach to the treatment of AMI. Administered acutely by the i.v. route at the time of PCI/CABG, PDE78INH has the potential to reduce infarct size by reducing reperfusion injury.
- © 2013 by American Heart Association, Inc.