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 A(1) receptor activation protect s against the cardiodepressant effects of hydrogen peroxide in isolate d rat hearts. The present study examined whether a transient ischemic period of 5 min duration, which preconditions the heart against ischem ic 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 pres ence of the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thiogua nosine and the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-no nyl)adenine, a significant attenuation of the hydrogen peroxide-induce d loss in contractility was evident and this was associated with signi ficant 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 A(1) receptor antag onist 8-cyclopentyl-1,3-dipropylxanthine as well as by glibenclamide, a blocker of the ATP-sensitive potassium channel (K-ATP). To further a ssess the role of glycogen in the protection against hydrogen peroxide , we compared the effects of the adenosine A(1) agonist N-6-cyclopenty l adenosine (CPA) and insulin. While both treatments protected against hydrogen peroxide the effect of insulin was superior to any other tre atment. Moreover, while all protective modalities preserved glycogen s tores after hydrogen peroxide treatment, the protection afforded by in sulin 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 tog ether, our results demonstrate that a brief period of ischemia with co ncomitant administration of agents which increase interstitial adenosi ne levels protects against hydrogen peroxide toxicity. The effect is m ediated by activation of adenosine A(1) receptors and is linked to K-A TP stimulation. Moreover, our results are strongly suggestive of an im portant role of glycogen preservation in bestowing protective effects against hydrogen peroxide cardiotoxicity. (C) 1996 Academic Press Limi ted