Adenosine kinase phosphorylates
adenosine to
AMP, the primary pathway for
adenosine metabolism under basal conditions. Inhibition of
adenosine kinase results in a site-specific increase in interstitial
adenosine. Using a rat model of
myocardial infarction, we examined the protective effects of
adenosine kinase inhibition. Male Sprague-Dawley rats underwent 30 min regional occlusion followed by 90 min reperfusion.
Infarct size, expressed as a percent of the area-at-risk, IS/AAR(%), was 58.0 +/- 2.1 % in untreated rats. Pretreatment with the
adenosine kinase inhibitor,
5-iodotubercidin (1 mg/kg), limited
infarct development to 37.5+/-3.7% (P < 0.001). The A(1)
adenosine receptor (A(1)AR) antagonist,
DPCPX (100 microg/kg), abolished the
infarct-sparing effect of
5-iodotubercidin (IS, 62.8 +/- 1.3%). Similarly, the A(3)
adenosine receptor (A(3)AR) antagonist, MRS-1523 (2 mg/kg), and the
delta-opioid receptor (DOR) antagonist, BNTX, (1 mg/kg) abolished the reduction of IS produced by iodotubercidin. Pretreatment with the ROS scavenger, 2-MPG (20 mg/kg), or the PKC-delta antagonist,
rottlerin (0.3 mg/kg) also abolished iodotubercidin-mediated cardioprotection. Furthermore, pretreatment with 5-HD, a mitochondrial K(
ATP) (
mitoK(ATP)) channel inhibitor, but not the sarcolemmal K(
ATP) channel blocker,
HMR-1098, abrogated the beneficial effects of
adenosine kinase inhibition (IS, 59.5 +/- 3.8%). These data suggest that inhibition of
adenosine kinase is effective in reducing
infarct development via A(1)AR, A(3)AR and DOR activation. Data also suggest that this protection is mediated via ROS, PKC-delta and
mitoK(ATP) channels.