Protection against injury during ischemia and reperfusion by acadesine derivatives GP-1-468 and GP-1-668 : studies in the transplanted rat heart

Acadesine (AICAr: 5-amino-4-imidazole carboxamide riboside) has been shown to afford sustained protection against injury during ischemia and reperfusion. The present studies used the heterotopically transplanted rat heart to assess the protective properties of two new acadesine analogs: GP-1-468 and GP-1-668. Hearts were excised, arrested with a 2-minute infusion of cardioplegic solution, and subjected to 4 hours of global ischemia (20 degrees C) with cardioplegic reinfusion for 2 minutes every 30 minutes. The hearts were then transplanted (1 hour of additional ischemia) into the abdomens of recipient rats and reperfused in situ for 30 minutes or 24 hours. The hearts were then excised, perfused aerobically for 20 minutes, and contractile function was assessed. GP-1-468 or GP-1-668 was administered to donor rats (20 mg/kg intravenously, 30 minutes before excision). They were also added to the cardioplegic solution (10 mumol/L for GP-1-468, 5 mumol/L for GP-1-343, the active metabolite of GP-1-668) and were also given to recipient rats (20 mg/kg intravenously, 30 minutes before transplantation, so that the drugs were present during reperfusion). Nine groups of hearts were studied. Three groups of studies were carried out (n = 24 transplants for each group). The first group of hearts was reperfused for 30 minutes, the second group was reperfused for 24 hours, and the third group was transplanted but not reperfused; instead, they were frozen at the end of 5 hours of ischemia and taken for metabolite analysis. Within each group were three subgroups (n = 8 per group) receiving GP-1-468, GP-1-668, or saline solution. In the 30-minute reperfusion group the recoveries of left ventricular developed pressure were 88 +/- 4, 87 +/- 7, and 50 +/- 9 mm Hg, respectively (p < 0.05 versus saline-treated controls); left ventricular volumes (recorded at 12 mm Hg) were 112 +/- 20, 132 +/- 28, and 41 +/- 9 microliters, respectively (p < 0.05 versus saline-treated controls), and coronary flows were 13.1 +/- 0.7, 13.4 +/- 1.0, and 9.9 +/- 0.5 ml/min, respectively (p < 0.05 versus saline-treated controls). In addition to improving functional recovery, the two analogs increased the tissue content of adenosine at the end of the ischemic period (5.4 +/- 0.6 and 7.3 +/- 0.5 mumol/gm dry weight, respectively, versus 2.7 +/- 0.4 mumol/gm dry weight in the saline-treated controls; p < 0.05); however, they did not influence adenosine triphosphate or its catabolites. In the 24-hour reperfu