Recent studies have indicated that activation of A1/A2-receptors may mediate metabolic adaptation of the heart to
ischemia/reperfusion stress. This study tests whether pretreatment with A1-selective agonist R(-)-N6-(2-phenylisopropyl)
adenosine (
R-PIA) might mimic effects of a brief period of
coronary occlusion (ischemic preconditioning, IP) on energy metabolism and
hydroxyl radical (
OH.) formation in canine myocardium following subsequent prolonged
ischemia and reperfusion. Anaesthetized dogs were randomized to a control group subjected to 40-min occlusion of a diagonal branch of left anterior descending coronary artery (LAD) followed by 1-h reperfusion, or a preconditioned group (PC) in which the same period of sustained
ischemia and reperfusion was preceded by a single cycle of IP (5-min occlusion of the same LAD branch and 10-min reperfusion), or to PIA group in which
R-PIA infusion into the same branch of LAD (0.4 microg/kg per min during 5 min) was followed by 10 min of perfusion prior to sustained
ischemia-reperfusion. Pretreatment with
R-PIA similarly to IP reduced
lactate (Lac),
creatine (Cr) and
inorganic phosphate (Pi) release from myocytes into the interstitial fluid during sustained
ischemia compared to these indices in control. By the end of reperfusion, both IP and
R-PIA infusion enhanced recovery of myocardial
ATP and
phosphocreatine (PCr) and attenuated the total
creatine (sigmaCr = PCr + Cr) loss, an index of cell membrane damage. A1-receptor activation by
R-PIA, as IP, led to a significant reduction in
OH. radical generation following reperfusion assessed by a spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) using cardiac microdialysis.
R-PIA pretreatment did not affect systemic and cardiac hemodynamic parameters. We conclude that (1) adaptive mechanisms of IP involve A1-receptor activation that contributes to the overall metabolic response and (2)
R-PIA acts as a useful preconditioning-mimetic and anti-ischemic agent in dogs.