Acadesine reduces myocardial infarct size by an adenosine mediated mechanism

Abstract

The aim was to test the hypotheses that acadesine (1) augments endogenous interstitial fluid (ISF) adenosine during ischaemia, and (2) reduces infarct size by adenosine receptor mediated mechanisms. To test these hypotheses, the left coronary artery of anaesthetised rabbits (n = 33) was occluded for 30 min and reperfused for 120 min. Acadesine (1 mg.kg-1.min-1 for 5 min, then 0.2 mg.kg-1.min-1) was infused intravenously beginning 30 min before coronary occlusion and ending 30 min after reperfusion. The area at risk was comparable in all groups, averaging 34.7 (SEM 2.2%) of the left ventricle. In separate studies (n = 22), estimates of ISF adenosine and adenosine metabolites were obtained by cardiac microdialysis. Although dialysate adenosine levels increased significantly in the area at risk during ischaemia in the untreated group [from 0.044(0.008) to 0.339(0.146) microM], acadesine did not significantly augment dialysate adenosine levels before or during ischaemia [preischaemia = 0.094(0.032) microM; ischaemia = 0.542(0.262) microM]. In addition, there was no significant difference in dialysate adenosine concentrations during the first 10 min of reperfusion, after which adenosine levels returned to baseline levels. A 2.5-fold large dose failed to increase interstitial fluid adenosine. However, the adenosine receptor blocker 8-p-sulphophenyltheophylline (SPT) in the presence of acadesine increased ISF adenosine fourfold. Acadesine significantly (P < 0.05) reduced infarct size [n = 8, 19.7(2.9)% of risk area] compared with the untreated group [n = 8, 29.4(1.3)%]. This infarct size reduction with acadesine was antagonised by SPT given during ischaemia-reperfusion [n = 8, 46.2(3.0)%] or only during reperfusion [n = 9, 42.7(2.6)%. Acadesine reduces infarct size by an adenosine mediated mechanism, but this cardioprotective action is not associated with significantly augmented interstitial fluid adenosine levels.