K-ATP CHANNELS AND MEMORY OF ISCHEMIC PRECONDITIONING IN DOGS - SYNERGISM BETWEEN ADENOSINE AND K-ATP CHANNELS

Results from numerous studies have shown that there is an important li nk between adenosine Al receptors and ATP-sensitive potassium (K-ATP) channels in mediating the cardioprotective effects of ischemic precond itioning (PC). The major aim of the present study was to determine whe ther occupation of A(1) receptors and/or the opening of K-ATP channels is involved in the time delay between the PC stimulus and the prolong ed ischemic insult or the ''memory'' of PC to reduce infarct size. Bar bital sodium-anesthetized dogs were subjected to 1 h of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfus ion. Ischemic PC was elicited by 10 min of LAD occlusion followed by 1 h of reperfusion (1-h memory) before the 1-h occlusion period. Either adenosine (800 g/min), bimakalim (3 g/min), a combination of two lowe r doses of each agent (400 g/min of adenosine and 0.3 g/min of bimakal im), or an equivalent volume of saline was infused into the LAD for 10 min followed by a 1-h drug-free period before the 1-h ischemic insult . In another series, glibenclamide, 8-cyclopentyl-1,3-dipropylxanthine (a selective A(1)-receptor blocker), or PD-115199 (a nonselective ade nosine-receptor antagonist) was administered 50 min after ischemic PC (10 min before the 1-h occlusion period). Infarct size (IS) was expres sed as a percentage of the area at risk. PC with 1 h of reperfusion re sulted in a marked reduction in ES (8.1 +/- 6.5 vs. 29.8 +/- 5.8% in c ontrol dogs). Administration of adenosine or bimakalim followed by a 1 -h drug-free period had no effect on IS; however, the simultaneous adm inistration of adenosine and bimakalim resulted in a marked decrease i n IS (11.5 +/- 2.7%). One hour after ischemic PC, administration of gl ibenclamide blocked the protective effect of ischemic PC, whereas 8-cy clopentyl-1,3-dipropylxanthine or PD-115199 did not affect it. These r esults provide evidence that the opening of myocardial K-ATP channels may play an important role in the memory of ischemic PC in the canine heart and also suggest that adenosine and the K-ATP channel may have a synergistic interaction that is important for the memory phase of PC.