Myocardial protection by adenosine triphosphate-sensitive potassium channel opener diazoxide involves sulfonylurea...

Pharmacologic openers of adenosine triphosphate-sensitive potassium (K_ATP) channels mimic ischemic preconditioning and are cardioprotective. The components of any relevant channel have not been identified, although several candidate protein targets have been proposed. Identification of implicated K_ATP channel components would allow directed drug targeting for clinical trials. We have investigated various channel subunits (Kir1.1, SUR1, Kir6.1, Kir6.2) as candidates, but none has been implicated. To complete our evaluation of recognized K_ATP channel components, we examined the potential role of the regulatory sulfonylurea receptor SUR2 in diazoxide (DZX) cardioprotection in a model of prolonged global myocardial ischemia.

Mice lacking SUR2 (knockout) and wild-type litter mates (genotype confirmed) were randomly assigned to 90 minutes of global ischemia in a Langendorff model after hypothermic hyperkalemic cardioplegia with or without DZX (100 μM/L) (N = 9-14 per group). Left ventricular developed pressure, end-diastolic pressure, and coronary flow were compared before and after global ischemia. Data acquisition and interpretation were blinded.

Prolonged global ischemia with cardioplegia was associated with reduced left ventricular developed pressure and increased end-diastolic pressure that was prevented by DZX in wild-type but not SUR2 knockout hearts, consistent with DZX cardioprotection being mediated by a K_ATP channel with a SUR2 component.

Cardioprotection provided by DZX was lost with genetic deletion of SUR2, implicating SUR2 as a subunit of a cardioprotective K_ATP channel. Identification of the subunits of a cardioprotective K_ATP channel would allow targeted pharmacologic therapy to reduce myocardial stunning after global ischemia during cardiac surgery.