(Circulation. 2001;103:3111.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Glimepiride, a Novel Sulfonylurea, Does Not Abolish Myocardial Protection Afforded by Either Ischemic Preconditioning or Diazoxide
From the Hatter Institute for Cardiovascular Studies (M.M.M., H.L.M., G.F.B., D.M.Y.), University College London Hospital and Medical School, London, and the Department of Cell Physiology and Pharmacology (C.L.L., N.B.S.), University of Leicester, Leicester, UK.
Correspondence to Prof Derek M. Yellon, Hatter Institute for Cardiovascular Studies, Division of Cardiology, University College London Hospitals and Medical School, Grafton Way, London WC1E 6DB, UK. E-mail hatter-institute{at}ucl.ac.uk
Background—The sulfonylurea glibenclamide (Glib) abolishes the cardioprotective effect of ischemic preconditioning (IP), presumably by inhibiting mitochondrial KATP channel opening in myocytes. Glimepiride (Glim) is a new sulfonylurea reported to affect nonpancreatic KATP 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 KATP 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 µmol/L Diaz, (4) 10 µmol/L Glim, (5) 10 µmol/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±4.7%, P<0.01). The protective actions of IP or Diaz were not abolished by Glim (18.5±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 (each at 1 µmol/L) blocked sarcolemmal KATP currents. However, in isolated cardiac mitochondria, Glim (10 µmol/L) failed to block the effects of KATP 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 KATP 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.
Key Words: potassium • myocardial infarction • diabetes mellitus • ion channels
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