Cardioprotection following adenosine kinase inhibition in rat hearts.
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.
Peart
J N
JN
Department of Pharmacology & Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. ggross@mcw.edu
Gross
G J
GJ
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D017202:Myocardial Ischemia / Q000517:prevention & control; D015221:Potassium Channels / Q000502:physiology; D020011:Protective Agents / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D051745:Protein Kinase C-delta; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D015221:Potassium Channels; D020011:Protective Agents; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; C497260:Prkcd protein, rat; D000248:Adenosine Kinase; D011493:Protein Kinase C; D051745:Protein Kinase C-delta