Sustained protection by acadesine against ischemia- and reperfusion-induced injury. Studies in the transplanted rat heart

Abstract

Background: We have shown that acadesine (AICAr: 5-amino-4-imidazole carboxamide riboside) improves the early recovery of function of the ischemic and reperfused rat heart. In the present studies we used the transplanted rat heart, with reperfusion for up to 24 hours, to assess whether the beneficial effect of acadesine is a transient or a sustained phenomenon (i.e., to determine whether the drug improves the extent of recovery or only the rate).

Methods and results: Hearts (n = 8 per group) were excised and immediately arrested with an infusion (2 minutes at 20 degrees C) of the St. Thomas' Hospital cardioplegic solution with or without the addition of acadesine (20 mumol/l). They were then subjected to 4 hours of global ischemia (20 degrees C), and the cardioplegic solution (with or without acadesine) was infused for 2 minutes every 30 minutes. The hearts then were transplanted (1 hour additional ischemic time) into the abdomens of recipient rats, which had been given acadesine (100 mg/kg i.v.) or saline. They were reperfused in situ for 30 minutes or 24 hours and then excised and perfused aerobically for 20 minutes. Contractile function was assessed, and the hearts were taken for metabolite analysis. Two sets of four groups (n = 8 per group) were studied (one set with 30 minutes and the other with 24 hours of reperfusion): group A, acadesine-free control; group B, acadesine during cardioplegia alone; group C, acadesine during reperfusion alone; and group D, acadesine during both cardioplegia and reperfusion. With 30 minutes of reperfusion, a significant improvement in functional recovery was seen in the two groups (groups B and D) in which acadesine had been added to the cardioplegic solution. Left ventricular developed pressure (LVDP) at 12 mm Hg of left ventricular end-diastolic pressure (LVEDP) was 104 +/- 3 mm Hg in both groups versus 88 +/- 3 mm Hg in the acadesine-free controls (p less than 0.05). No protection was observed after 30 minutes of reperfusion when acadesine had been added during reperfusion alone (89 +/- 4 mm Hg). In contrast, after 24 hours of reperfusion there was a significant improvement in postischemic LVDP in all acadesine-treated groups (group B, 104 +/- 6 mm Hg; group C, 106 +/- 7 mm Hg; and group D, 117 +/- 3 mm Hg versus only 73 +/- 6 mm Hg in the acadesine-free controls; p less than 0.05 in each case). Metabolite analysis indicated that at the end of ischemia ATP was less depleted and levels of tissue adenosine were higher in the acadesine group. During early (30 minutes) reperfusion, acadesine produced higher mean ATP contents, although this achieved a level of statistical significance only when the drug was administered during both cardioplegia and reperfusion. After 24 hours of reperfusion, the adenine nucleotide pools were similar in all groups.

Conclusions: Acadesine can afford sustained functional protection against injury during extended periods of ischemia and reperfusion. We present evidence that the beneficial effect of acadesine may be mediated by two different components, with one operative during ischemia and early reperfusion and the other acting later in the reperfusion period.