Mocanu, MM; Maddock, HL; Baxter, GF; Lawrence, CL; Standen, NB; Yellon, DM; (2001) Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide. CIRCULATION , 103 (25) 3111 - 3116.
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Background-The sulfonylurea glibenclamide (Glib) abolishes the cardioprotective effect of ischemic preconditioning (IP), presumably by inhibiting mitochondrial K-ATP channel opening in myocytes. Glimepiride (Glim) is a new sulfonylurea reported to affect nonpancreatic K-ATP channels less than does Glib. We examined the effects of Glim on IP and on the protection afforded by diazoxide (Diaz), an opener of mitochondrial K-ATP channels.Methods and Results-Rat hearts were Langendorff-perfused, subjected to 35 minutes 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 each 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). However, Glib abolished the infarct-limiting effects of IP and Diaz, Patch-clamp studies in isolated rat ventricular myocytes confirmed that both Glim and Glib teach at 1 <mu>mol/L blocked sarcolemmal K-ATP currents. However, in isolated cardiac mitochondria, Glim(10 mu mol/L) failed to block the effects 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 implications for the treatment of type 2 diabetes in patients with ongoing ischemic heart disease.
|Title:||Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide|
|Keywords:||potassium, myocardial infarction, diabetes mellitus, ion channels, SENSITIVE K+ CHANNELS, MITOCHONDRIAL-FUNCTION, HYPOGLYCEMIC AGENTS, POTASSIUM CHANNELS, BLOOD-GLUCOSE, ATP CHANNEL, GLIBENCLAMIDE, COMPLICATIONS, DERIVATIVES, MEMBRANE|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology|
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
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