Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide

Background-The sulfonylurea glibenclamide (Glib) abolishes the cardioprotec tive effect of ischemic preconditioning (IP), presumably by inhibiting mito chondrial K-ATP channel opening in myocytes. Glimepiride (Glim) is a new su lfonylurea reported to affect nonpancreatic K-ATP channels less than does G lib. We examined the effects of Glim on IP and on the protection afforded b y diazoxide (Diaz), an opener of mitochondrial K-ATP channels. Methods and Results-Rat hearts were Langendorff-perfused, subjected to 35 m inutes of regional ischemia and 120 minutes of reperfusion, and assigned to 1 of the following treatment groups: (1) control; (2) IP of 2X 5 minutes e ach of global ischemia before lethal ischemia, or pretreatment with (3) 30 mu mol/L Diaz, (4) 10 mu mol/L Glim. (5) 10 mu mol/L Glib, (6) IP+Glim, (7) IP+Glib, (8) Diaz+Glim, or (9) Diaz+Glib. IP limited infarct size (18.5 +/ -1% vs 43.7 +/-3% in control, P<0.01) as did Diaz (22.2<plus/minus>4.7%. P< 0.01), The protective actions of IP or Diaz were not abolished by Glim (18. 5<plus/minus>3% in IP+Glim, 22.3 +/-3% in Diaz+Glim; P<0.01 vs control). Ho wever, Glib abolished the infarct-limiting effects of IP and Diaz, Patch-cl amp studies in isolated rat ventricular myocytes confirmed that both Glim a nd Glib teach at 1 <mu>mol/L blocked sarcolemmal K-ATP currents. However, i n isolated cardiac mitochondria, Glim(10 mu mol/L) failed to block the effe cts of K-ATP opening by GTP, in contrast to the blockade caused by Glib. Conclusions-Although it blocks sarcolemmal currents in rat cardiac myocytes . Glim does not block the beneficial effects of mitochondrial K-ATP channel opening in the isolated rat heart. These data may have significant implica tions for the treatment of type 2 diabetes in patients with ongoing ischemi c heart disease.