Abstract 3006: The Adenosine Regulating Agent GP531 Reduces Post Ischemia/Reperfusion Necrosis and Extent of No-reflow Without Adverse Hemodynamic Effects
Adenosine is an effective adjunctive therapy for myocardial infarction (MI), but its use is limited by a short half-life and adverse effects on hemodynamics (hypotension and bradycardia). A new class of cardioprotective agents, adenosine regulating agents (ARA), has been developed that increase local endogenous adenosine levels during net ATP depletion, such as occurs during regional ischemia but remain biologically silent under normal conditions. Acadesine, the prototype ARA, has been shown to improve long-term survival in CABG patients who experience perioperative MI. GP531 is a potent second generation ARA that has been shown to increase local endogenous adenosine levels and has a longer half-life than acadesine. Our objective was to determine whether GP531 reduces the extent of MI and the anatomic no-reflow zone, and to evaluate its effects on regional myocardial blood flow (RMBF) in the anesthetized rabbit. GP531 was given as a 10 min bolus followed by infusion at two doses (700 μg/kg and 10 μg/kg/min or 2100 μg/kg and 30 μg/kg/min) or vehicle alone, starting at 12 min before a 30-min coronary artery occlusion and 3 hrs of reperfusion in the open-chest, anesthetized rabbit. The ischemic risk zone was delineated by blue dye injected into the vasculature, necrosis by triphenyltetrazolium chloride staining, and RMBF with radioactive microspheres. The anatomic no-reflow zone (non-fluorescent) was assessed by thioflavin S, injected IV with the epicardial artery open. The extent of the ischemic risk zone was similar in all groups. Low dose GP531 reduced infarct size by 36% (33±4 % of the risk zone) compared with vehicle (50±4%, p <0.005) and reduced the extent of the anatomic no-reflow zone (areas unstained by thioflavin S) by 29% compared with vehicle (25±3 % of the risk zone vs. 36±4 % in the vehicle group, p=0.05). Mean infarct size and the zone of no-reflow in the high dose group was intermediate between low dose and vehicle, reducing infarct size by 29% and the zone of no-reflow by 14%. GP531 did not cause hypotension, bradycardia or coronary steal, and RMBF was similar in all groups at all time points. Thus, the ARA, GP531, markedly reduced MI and decreased the anatomic no-reflow zone without the adverse systemic effects associated with adenosine treatment.