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Cardioprotection following adenosine kinase inhibition in rat hearts

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Abstract

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 A1 adenosine receptor (A1AR) antagonist, DPCPX (100 µg/kg), abolished the infarct–sparing effect of 5–iodotubercidin (IS, 62.8 ± 1.3%). Similarly, the A3 adenosine receptor (A3AR) antagonist, MRS–1523 (2 mg/kg), and the δ–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–δ antagonist, rottlerin (0.3 mg/kg) also abolished iodotubercidin–mediated cardioprotection. Furthermore, pretreatment with 5–HD, a mitochondrial KATP (mitoKATP) channel inhibitor, but not the sarcolemmal KATP 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 A1AR, A3AR and DOR activation. Data also suggest that this protection is mediated via ROS, PKC–δ and mitoKATP channels.

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Authors and Affiliations

  1. Department of Pharmacology & Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, Wi. 53226, USA

    J. N. Peart Ph.D & G. J. Gross Ph.D.

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  1. J. N. Peart Ph.D
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  2. G. J. Gross Ph.D.
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Correspondence to G. J. Gross Ph.D..

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Peart, J.N., Gross, G.J. Cardioprotection following adenosine kinase inhibition in rat hearts. Basic Res Cardiol 100, 328–336 (2005). https://doi.org/10.1007/s00395-005-0526-7

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