Transient ischemia in the presence of an adenosine deaminase plus a nucleoside transport inhibitor confers protection against contractile depression produced by hydrogen peroxide. Possible role of glycogen.
We previously reported that adenosine A1 receptor activation protects against the cardiodepressant effects of hydrogen peroxide in isolated rat hearts. The present study examined whether a transient ischemic period of 5 min duration, which preconditions the heart against ischemic and reperfusion-induced dysfunction, can bestow protection against 30-min exposure to hydrogen peroxide in isolated rat hearts. Transient ischemia on its own failed to alter the cardiac response to hydrogen peroxide. However, when transient ischemia was carried out in the presence of the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thioguanosine and the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-nonyl)adenine, a significant attenuation of the hydrogen peroxide-induced loss in contractility was evident and this was associated with significant preservation of tissue glycogen content. The protective effect of the transient ischemia/drug combination on both functional changes and glycogen levels was abolished by the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine as well as by glibenclamide, a blocker of the ATP-sensitive potassium channel (KATP). To further assess the role of glycogen in the protection against hydrogen peroxide, we compared the effects of the adenosine A1 agonist N6-cyclopentyl adenosine (CPA) and insulin. While both treatments protected against hydrogen peroxide the effect of insulin was superior to any other treatment. Moreover, while all protective modalities preserved glycogen stores after hydrogen peroxide treatment, the protection afforded by insulin was also associated with significantly elevated glycogen levels prior to hydrogen peroxide administration. No protection by either CPA or insulin was evident in the absence of exogenous glucose. Taken together, our results demonstrate that a brief period of ischemia with concomitant administration of agents which increase interstitial adenosine levels protects against hydrogen peroxide toxicity. The effect is mediated by activation of adenosine A1 receptors and is linked to KATP stimulation. Moreover, our results are strongly suggestive of an important role of glycogen preservation in bestowing protective effects against hydrogen peroxide cardiotoxicity.
Gan
X T
XT
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Cook
M A
MA
Moffat
M P
MP
Karmazyn
M
M
D000243:Adenosine Deaminase / Q000494:pharmacology*; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006003:Glycogen / Q000502:physiology*; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D016877:Oxidants / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013872:Thionucleosides / Q000494:pharmacology*
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D016877:Oxidants; D013872:Thionucleosides; D006151:Guanosine; D006003:Glycogen; D006861:Hydrogen Peroxide; D000243:Adenosine Deaminase