PROTECTION AGAINST INJURY DURING ISCHEMIA AND REPERFUSION BY ACADESINE DERIVATIVES GP-1-468 AND GP-1-668 - STUDIES IN THE TRANSPLANTED RAT-HEART

Background. 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. Methods and results. Hearts were excised, arrested with a 2-minute infusion of cardioplegic solut ion, and subjected to 4 hours of global ischemia (20 degrees C) with c ardioplegic reinfusion for 2 minutes every 30 minutes. The hearts were then transplanted (1 hour of additional ischemia) into the abdomens o f recipient rats and reperfused in situ for 30 minutes or 24 hours. Th e hearts were then excised, perfused aerobically for 20 minutes, and c ontractile function was assessed. GP-1-468 or GP-1-668 was administere d to donor rats (20 mg/kg intravenously, 30 minutes before excision). They were also added to the cardioplegic solution (10 mu mol/L for GP- 1-468, 5 mu mol/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 reperfu sion). Nine groups of hearts were studied. Three groups of studies wer e 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 develop ed pressure were 88 +/- 4, 87 +/- 7, and 50 +/- 9 mm Hg, respectively (p < 0.05 versus saline-treated controls); left ventricular volumes (r ecorded at 12 mm Hg) were 112 +/- 20, 132 +/- 28, and 41 +/- 9 mu l, r espectively (p < 0.05 versus saline-treated controls), and coronary fl ows were 13.1 +/- 0.7, 13.4 +/- 1.0, and 9.9 +/- 0.5 ml/min, respectiv ely (p < 0.05 versus saline-treated controls). In addition to improvin g 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 mu mol/gm dry weight, respectively, versus 2.7 +/- 0.4 mu mol/gm d ry weight in the saline-treated controls; p < 0.05); however, they did not influence adenosine triphosphate or its catabolites. In the 24-ho ur reperfusion group the corresponding values were 77 +/- 6 and 88 +/- 6 versus 35 +/- 4 mm Hg for left ventricular developed pressure (p < 0.05), 111 +/- 9 and 121 +/- 11 versus 41 +/- 8 mu l for left ventricu lar volume (p < 0.05), and 13.7 +/- 0.7 and 13.0 +/- 0.6 versus 11.7 /- 0.7 ml/min for coronary flow (no significant difference). Thus both analogs afforded an early and comparable degree of protection of cont ractile function that was sustained even after 24 hours of reperfusion . Conclusions. Both GP-1-468 and GP-1-668 increase the rate and extent of early postischemic recovery, and this protection is sustained for at least 24 hours. These beneficial actions were associated with an in crease of the tissue content of adenosine during ischemia, but they ap peared to be independent of the status of the high-energy metabolism.