Acadesine attenuates ischemic cardiac dysfunction in the isolated blood-perfused rabbit heart

Acadesine (AICA-riboside) is a nucleoside analog with cardioprotective properties. Most previous studies demonstrating cardioprotection with acadesine have been conducted in buffer-perfused hearts, and no study has investigated the dose-response relationship to acadesine in a blood-perfused model. The objective of this study was to investigate the dose-related cardioprotective effects of acadesine in donor-perfused, isolated rabbit hearts subjected to 12 × 3 min episodes of global ischemia with intervening periods of reperfusion of 5 min duration. Five groups of hearts were studied: saline control and four treatment groups of acadesine, 0.1, 0.2, 0.5, 2.0 gm/kg/min (0.4, 0.8, 2.0, 8.0 μmol/kg/min) constant intravenous infusion to the support animal. Left ventricular (LV) pressure and coronary blood flow (CBF) in the isolated hearts were measured. In control hearts, baseline LV developed pressure averaged 129 ± 7 mmHg and declined to 43 ± 3% of baseline after 12 periods of ischemia and reperfusion. Acadesine significantly improved recovery of function at the lower doses tested, i.e., hearts treated with 0.1, 0.2, and 0.5 mg/kg/min (0.4, 0.8, 2.0 μmol/kg/min) recovered 61 ± 5%, 67 ± 7%, and 65 ± 7% of LV pressure, respectively (P < 0.05 vs. saline). This protective effect was not observed with the highest dose of acadesine, 2.0 mg/kg/min (8.0 μmol/kg/min) (52 ± 6%). The greatest recovery of function corresponded to plasma acadesine concentrations of 27 ± 6.0 μM, but the beneficial effect was lost when plasma concentrations reached 205 ± 28 μM. These results suggest that repetitive episodes of ischemia and reperfusion induced stunning in isolated blood-perfused rabbit hearts, and that the severity of this dysfunction is attenuated by treatment with acadesine. © 1994 Wiley-Liss, Inc.