PROTECTION FROM ISCHEMIC-REPERFUSION INJURY WITH ADENOSINE PRETREATMENT IS REVERSED BY INHIBITION OF ATP-SENSITIVE POTASSIUM CHANNELS

Objective: The aim was to test the hypothesis that the cardioprotectiv e effects against ischaemic-reperfusion injury of pretreatment with ad enosine are mediated in part by activation of ATP sensitive potassium channels (K+ATP channels). Methods: 42 anaesthetised New Zealand White rabbits underwent 30 min coronary occlusion, followed by 2 h reperfus ion. Half the animals received a 5 min infusion of 140 mug.kg-1.min-1 of adenosine as pretreatment. The remainder of the animals received a 5 min infusion of saline alone as pretreatment. Animals pretreated wit h adenosine received either a low dose of the K+ATP channel blocker gl ibenclamide (0.3 mg.kg-1), high dose glibenclamide (3.0 mg.kg-1), or v ehicle immediately prior to ischaemia to test whether glibenclamide ca n reverse the protective effects of adenosine, thus allowing the adeno sine effect but antagonising K+ATP channel activation during ischaemia . Animals which received saline pretreatment also received low dose gl ibenclamide, high dose glibenclamide, or vehicle (controls) to evaluat e the effect of glibenclamide alone. Infarct size was determined with tetrazolium and Unisperse Blue stains, and transmural blood flow was m easured using radioactive microspheres. Results: Although there were n o differences in collateral myocardial blood flow during ischaemia or in risk area among the groups, infarct size was reduced by adenosine p retreatment to 8 (SEM 3)% v 36(4)% in controls (p<0.05). K+ATP channel blockade with low dose glibenclamide in saline pretreated animals did not by itself extend the degree of necrosis [33(4)%], whereas low dos e glibenclamide prevented the protective effects of adenosine pretreat ment [38(3)%]. High dose glibenclamide reversed adenosine protection a s well [54(3)%], but at a dose which increased infarct size in saline pretreated animals [52(3)%]. Conclusions: While adenosine pretreatment protects against necrosis in the rabbit, (1) the expression of this p rotection depends at least in part upon the actions of K+ATP channels during ischaemia, and (2) glibenclamide at higher doses increases infa rct size, suggesting either that the K+ATP channel is endogenously pro tective during ischaemia, or that the higher dose has other infarct ex tending effects.