We used
adenosine A1 receptor agonist N6-1(phenyl-2R-isopropyl)-adenosine (PIA), A1 receptor antagonist
8-cyclopentyl-1,3-dipropylxanthine (
DPCPX), and
ATP-sensitive K+ (
KATP) channel blockers
sodium 5-hydroxydecanoate (5-HD) and
glibenclamide (Glib), as probes to investigate the role and mechanism of
adenosine in ischemic preconditioning (IPC) of noncontractile skeletal muscle against
infarction, using the pig latissimus dorsi muscle flap model. Except for Glib, all drugs were delivered to each muscle flap by 10-min local
intra-arterial infusion to avoid systemic effects. Muscle flaps that were subjected to 4 h of global
ischemia and 48 h of reperfusion sustained 40 +/- 2%
infarction. IPC with three cycles of 10 min
ischemia and reperfusion, preischemic
adenosine, or PIA treatment reduced (P < 0.05) muscle
infarction to 24 +/- 2, 18 +/- 2, and 24 +/- 2%, respectively. The anti-
infarction effect of IPC and
adenosine was blocked by
DPCPX, 5-HD, and Glib (P < 0.05). Preischemic
adenosine treatment also maintained higher muscle contents of
phosphocreatine,
ATP, and energy charge potential and lower muscle contents of dephosphorylated metabolites and
lactate during
ischemia and a lower muscle
myeloperoxidase (MPO) activity during reperfusion compared with the control (P < 0.05). Preischemic
adenosine treatment did not increase muscle content of
adenosine during
ischemia or reperfusion. Furthermore,
adenosine given at the onset of reperfusion was not effective in attenuating muscle MPO activity or
infarction. Taken together, these observations indicate that
adenosine, through A1 receptors, initiates the mechanism of IPC with postreceptor involvement of
KATP channels in skeletal muscle. However,
adenosine is unlikely to play a key role in the effector mechanism. Presently, the cause and role of energy sparing and neutrophil inhibitory effects associated with the anti-
infarction effect of preischemic
adenosine treatment are unknown.