MYOCARDIAL PRECONDITIONING PRODUCED BY ISCHEMIA, HYPOXIA, AND A K-ATPCHANNEL OPENER - EFFECTS ON INTERSTITIAL ADENOSINE IN DOGS

Previous research has demonstrated that a transient increase in inters titial adenosine and subsequent activation of ATP-sensitive K+ (K-ATP) channels are involved in triggering ischemic preconditioning (PC), ho wever, the role of adenosine in mediating the cardioprotection of hypo xic FC and that produced by K-ATP channel openers is Less clear. Thus, the aim of the present study was to determine the role of adenosine i n mediating the cardioprotective effects of PC produced by 5 min of is chemia, hypoxia, or by a 5-min intracoronary (i.c.) infusion of the K- ATP channel opener bimakalim (1 mu g/min). A single microdialysis prob e was implanted into the midwall of the ischemic area for sampling olf interstitial fluid adenosine and its breakdown products during the PC stimulus, prolonged occlusion (60 min) and during the first 30 min of the reperfusion (3 h) period. Ischemic, hypoxic and bimakalim pretrea tment significantly reduced infarct size, 5.3 +/- 1.5, 8.9 +/- 2.5; 11 .4 +/- 3.2, respectively, as compared to control: 27.3 +/- 6.5. Both i schemic and hypoxic PC produced similar and significant increases (0.5 6 +/- 0.13 mu mol/l to 1.12 +/- 0.12 mu mol/l and 1.32 mu mol, control , ischemic and hypoxic PC, respectively) in dialysate adenosine concen tration which persisted during the brief 10-min reperfusion period fol lowing PC. However, i.c. bimakalim resulted in a significant decrease in dialysate adenosine (0.56 +/- 0.13 mu mol/l to 0.22 +/- 0.04 mu mol /l) which persisted during the 10-min drug-free period. All three PC p rotocols resulted in similar decreases in dialysate adenosine, inosine and uric acid concentrations throughout the prolonged ischemic period as compared to control animals. In conclusion (1): PC produced by isc hemia or hypoxia results in an increase in interstitial adenosine prio r to a prolonged occlusion period; (2) the K-ATP channel agonist, bima ltalim, significantly decreased interstitial adenosine prior to a prol onged occlusion period: (3) ischemic PC, hypoxic PC, and bimakalim pre treatment produced a similar reduction in interstitial adenosine and i ts breakdown products during the prolonged ischemic period. These resu lts suggest that an increase in interstitial adenosine may be necessar y for the initiation of the protective effect of ischemic and hypoxic PC but an increase in adenosine is not necessary for the cardioprotect ive effect of a direct opener of the K-ATP channel. (C) 1998 Academic Press.