Although the importance of
adenosine (
Ado)-receptor activation in preconditioning (PC) has been established, it is unclear whether cardioprotection afforded by PC is determined by the
Ado level during PC
ischemia or by that during sustained
ischemia. Accordingly, we tested whether the PC effect is modified by augmenting the increase in the interstitial
Ado level during PC or by that during sustained
ischemia. In the first series of experiments, the effect of 0.25 mg/kg
dipyridamole (DIP) on the interstitial
Ado level was assessed by in vivo microdialysis in the rabbit heart.
Dialysate Ado during 2-min
ischemia was 70% higher in the heart pretreated with 0.25 mg/kg of DIP than in the untreated controls, indicating that DIP was capable of enhancing an
ischemia-induced increase of interstitial
Ado. In the second series of experiments,
myocardial infarction was induced in the rabbit by 30-min coronary artery occlusion and 3-h reperfusion.
Infarct size was determined by tetrazolium staining and expressed as percentage of area at risk (%IS/AR). Rabbits were subjected to one of nine treatments before the 30-min
ischemia: no treatment, DIP (0.25 mg/kg, i.v.), PC with 2-min
ischemia, DIP before 2-min PC, DIP after 2-min PC, PC with 3-min
ischemia, DIP before 3-min PC, DIP after 3-min PC, or
8-sulfophenyltheophylline (SPT) after 3-min PC. DIP alone did not modify %IS/AR (38.8 +/- 5.8% vs. 41.2 +/- 4.7%), but administration of DIP before 2-min PC significantly enhanced the
infarct size-limiting effect (14.6 +/- 2.1% with DIP vs. 32.1 +/- 4.7% without DIP). Although the 3-min PC per se could achieve significant
infarct limitation, the effect of DIP on 3-min PC was not significant (14.7 +/- 1.9% with DIP vs. 20.5 +/- 1.8% without DIP). On the other hand, the effect of DIP administered after PC was very slight (only 7% reduction of %IS/AR) and statistically insignificant, regardless of the duration of PC
ischemia. However,
infarct limitation by 3-min PC was inhibited by SPT given after the PC (%IS/AR = 34.5 +/- 3.2), as reported previously. These results suggest that the interstitial
Ado level during PC
ischemia, not the level during sustained
ischemia, is a primary determinant of the extent of cardioprotection by PC and that the threshold for
Ado-receptor activation required during sustained
ischemia is much lower than that for triggering PC.