Circulation, Vol 86, 598-608, Copyright © 1992 by American Heart Association
M Galinanes, KM Mullane, D Bullough and DJ Hearse
BACKGROUND. Although there are many factors that might contribute to tissue
injury during ischemia and reperfusion, the loss of adenine nucleotides has
long been considered to be of importance. This has led to the study of
interventions designed to limit the loss of nucleotides or to enhance the
rate of nucleotide resynthesis during reperfusion. Alternatively, the
breakdown of adenosine triphosphate to adenosine might represent a
protective response of the ischemic heart because adenosine is considered
an anti-injury autocoid. Augmentation of endogenous adenosine levels might
be beneficial. For these reasons, the protective properties of acadesine
(AICAr: 5-amino-4-imidazole carboxamide riboside) were assessed in a rat
model of myocardial ischemia and reperfusion. METHODS AND RESULTS. The
protective properties of acadesine were studied in the isolated, perfused
rat heart subjected to global hypothermic (20 degrees C) ischemia and
reperfusion. When acadesine was given as an in vivo pretreatment (100 mg/kg
i.v. 15 minutes before study) followed by being administered as an additive
(20 mumol/l) to the St. Thomas' Hospital cardioplegic solution (single
dose) and then as an additive (20 mumol/l) to the initial reperfusion (15
minutes) solution, the recovery of aortic flow after 2.5 hours of ischemia
was improved from its control value of 16.5 +/- 3.9 ml/min to 28.9 +/- 4.1
ml/min (n = 8 per group; p less than 0.05). Similar protection was seen
with other indexes of cardiac function. Analysis of hearts obtained at the
end of 2.5 hours of ischemia and 35 minutes of reperfusion revealed no
significant differences in metabolite content between control and
drug-treated hearts with the exception of inosine monophosphate, which was
increased from its drug-free control value of 0.10 +/- 0.01 mumol/g dry wt
to 0.86 +/- 0.06 mumol/g dry wt (p less than 0.05). In further studies (n =
8 per group), with multidose (every 30 minutes) cardioplegia and extended
periods (6 hours) of hypothermic ischemia, acadesine consistently led to
higher mean recoveries of function and lower levels of creatine kinase
leakage. Again, the only significant metabolic effect was an increase in
tissue inosine monophosphate content. In studies (n = 12 per group) to
determine whether acadesine was acting before, during, or after ischemia,
the drug was given 1) only as pretreatment (100 mg/kg i.v.), 2) only during
single-dose cardioplegia (20 mumol/l), or 3) only during reperfusion (20
mumol/l). Significant protection was observed in the first two groups
(recovery of aortic flow increased from 10.6 +/- 2.6 ml/min in the
acadesine-free control to 22.6 +/- 2.8 and 23.6 +/- 3.1 ml/min,
respectively; p less than 0.05). No significant protection was observed
when acadesine was given only during reperfusion. In dose-response studies,
acadesine (0, 5, 20, 50, 200, and 1,000 mumol/l; n = 12 per group) was
given only as a cardioplegic additive; the postischemic recoveries of
aortic flow were 15.4 +/- 2.8, 16.9 +/- 3.6, 29.5 +/- 3.8, 27.4 +/- 3.8,
26.7 +/- 4.2, and 27.1 +/- 2.7 ml/min, respectively. CONCLUSIONS. Acadesine
improves the ability of the heart to recover from ischemia and reperfusion
when administered before ischemia or with cardioplegia. The mechanism
underlying the protection remains to be resolved.
ARTICLES
Acadesine and myocardial protection. Studies of time of administration and dose-response relations in the rat
Cardiovascular Research, Rayne Institute, St. Thomas' Hospital, London, UK.
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