ACADESINE REDUCES MYOCARDIAL INFARCT SIZE BY AN ADENOSINE-MEDIATED MECHANISM

Objective: The aim was to test the hypotheses that acadesine (1) augme nts endogenous interstitial fluid (ISF) adenosine during ischaemia and (2) reduces infarct size by adenosine receptor mediated mechanisms. M ethods: To test these hypotheses, the left coronary artery of anaesthe tised 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 co mparable in all groups, averaging 34.7(SEM 2.2%) of the left ventricle . In separate studies (n = 22), estimates of ISF adenosine and adenosi ne metabolites were obtained by cardiac microdialysis. Although dialys ate adenosine levels increased significantly in the area at risk durin g ischaemia in the untreated group [from 0.044(0.008) to 0.339(0.146) mu M], acadesine did not significantly augment dialysate adenosine lev els before or during ischaemia [preischaemia = 0.094(0.032) mu M; isch aemia = 0.542(0.262) mu M]. In addition, there was no significant diff erence in dialysate adenosine concentrations during the first 10 min o f reperfusion, after which adenosine levels returned to baseline level s. A 2.5-fold large dose failed to increase interstitial fluid adenosi ne. However, the adenosine receptor blocker 8-p-sulphophenyltheophylli ne (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)%. Conclusions: Acadesine reduces infarct size by an adenosine mediated mechanism, but this cardioprotective ac tion is not associated with significantly augmented interstitial fluid adenosine levels.