Effector mechanism of adenosine in acute ischemic preconditioning of skeletal muscle against infarction.

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.