Circulation, Vol 86, 589-597, Copyright © 1992 by American Heart Association
M Galinanes, D Bullough, KM Mullane and DJ Hearse
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.
ARTICLES
Sustained protection by acadesine against ischemia- and reperfusion- induced injury. Studies in the transplanted rat heart
Cardiovascular Research, Rayne Institute, St. Thomas' Hospital, London, UK.
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