Protection from ischaemic-reperfusion injury with adenosine pretreatment is reversed by inhibition of ATP sensitive potassium channels.

OBJECTIVE

The aim was to test the hypothesis that the cardioprotective effects against ischaemic-reperfusion injury of pretreatment with adenosine 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 reperfusion. Half the animals received a 5 min infusion of 140 micrograms.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 with adenosine received either a low dose of the K+ATP channel blocker glibenclamide (0.3 mg.kg-1), high dose glibenclamide (3.0 mg.kg-1), or vehicle immediately prior to ischaemia to test whether glibenclamide can reverse the protective effects of adenosine, thus allowing the adenosine effect but antagonising K(+)ATP channel activation during ischaemia. Animals which received saline pretreatment also received low dose glibenclamide, high dose glibenclamide, or vehicle (controls) to evaluate the effect of glibenclamide alone. Infarct size was determined with tetrazolium and Unisperse Blue stains, and transmural blood flow was measured using radioactive microspheres.

RESULTS

Although there were no differences in collateral myocardial blood flow during ischaemia or in risk area among the groups, infarct size was reduced by adenosine pretreatment 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 dose glibenclamide prevented the protective effects of adenosine pretreatment [38(3)%]. High dose glibenclamide reversed adenosine protection as 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 protection depends at least in part upon the actions of K(+)ATP channels during ischaemia, and (2) glibenclamide at higher doses increases infarct size, suggesting either that the K(+)ATP channel is endogenously protective during ischaemia, or that the higher dose has other infarct extending effects.