ACADESINE EXTENDS THE WINDOW OF PROTECTION AFFORDED BY ISCHEMIC PRECONDITIONING

Objective: The aim was to test whether acadesine (5-amino-4-imidazolecarboxamide riboside, AICAR), an adenosine regulating agent which increases tissue adenosine during ischaemia, could prolong the window of protection from ischaemic preconditioning. Methods: A branch of the left coronary artery of a rabbit heart was occluded for 30 min and reperfused for 180 min to induce infarction. Infarct size was determined with triphenyl tetrazolium staining. Prior to the 30 min ischaemia, rabbits were subjected to one of the following seven protocols: (1) No treatment (controls). (2) Preconditioning with 5 min of regional ischaemia followed by 2 h of reperfusion. (3) Treatment with acadesine (2.5 mg.kg(-1).min(-1) intravenously for 5 min starting 155 min prior to 30 min ischaemia followed by 210 min infusion of 0.5 mg.kg(-1).min(-1). (4) Treatment with acadesine (same schedule as in group 3) plus preconditioning as in group 2. (5) Treatment with acadesine for a shorter period (acadesine 2.5 mg.kg(-1).min(-1) for 5 min starting 30 min prior to preconditioning followed by 0.5 mg.kg(-1).min(-1) for only 60 min) plus preconditioning as in group 2. (6) Treatment with preconditioning followed by adenosine receptor blockade with 8-(p-sulphophenyl)theophylline (SPT) 10 mg.kg(-1) intravenously immediately after and again 15 min after preconditioning. (7) Treatment with short infusion of acadesine plus preconditioning plus SPT. Results: Preconditioning followed by 2 h of reperfusion offered little protection against infarction [28.6(SEM 2.7)% of the ischaemic zone infarcted] as compared to control [38.7(3.1)% infarction]. Treatment with acadesine alone did not modify the infarct size [37.8(3.5)%], but both of the acadesine plus preconditioning groups showed a significant limitation of infarct size with 13.9(3.1)% infarction in group 3 and 12.7(2.2)% infarction in group 5 (both p < 0.01 v control). Although SPT alone did not modify the infarct size [26.8(3.3)%], SPT blocked the protective effect of acadesine [25.3(2.9)%, p < 0.05 v group 5]. Conclusion: Acadesine can delay the natural decay of preconditioning. This delay appeared to be mediated by adenosine and may have therapeutic potential.