Previous research has demonstrated that a transient increase in interstitial
adenosine and subsequent activation of
ATP-sensitive K+ (
KATP) channels are involved in triggering ischemic preconditioning (PC), however, the role of
adenosine in mediating the cardioprotection of hypoxic PC and that produced by
KATP channel openers is less clear. Thus, the aim of the present study was to determine the role of
adenosine in mediating the cardioprotective effects of PC produced by 5 min of
ischemia,
hypoxia, or by a 5-min intracoronary (i.c.) infusion of the
KATP channel opener
bimakalim (1 microgram/min). A single microdialysis probe was implanted into the midwall of the ischemic area for sampling of 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 pretreatment 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 ischemic and hypoxic PC produced similar and significant increases (0.56 +/- 0.13 mumol/l to 1.12 +/- 0.12 mumol/l and 1.32 mumol, control, ischemic and hypoxic PC, respectively) in
dialysate adenosine concentration which persisted during the brief 10-min reperfusion period following PC. However, i.c.
bimakalim resulted in a significant decrease in
dialysate adenosine (0.56 +/- 0.13 mumol/l to 0.22 +/- 0.04 mumol/l) which persisted during the 10-min
drug-free period. All three PC protocols 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
ischemia or
hypoxia results in an increase in interstitial
adenosine prior to a prolonged occlusion period; (2) the
KATP channel agonist,
bimakalim, significantly decreased interstitial
adenosine prior to a prolonged occlusion period; (3) ischemic PC, hypoxic PC, and
bimakalim pretreatment produced a similar reduction in interstitial
adenosine and its breakdown products during the prolonged ischemic period. These results suggest that an increase in interstitial
adenosine may be necessary for the initiation of the protective effect of ischemic and hypoxic PC but an increase in
adenosine is not necessary for the cardioprotective effect of a direct opener of the
KATP channel.