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


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 micromol/L Diaz, (4) 10 micromol/L Glim, (5) 10 micromol/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 micromol/L) blocked sarcolemmal K(ATP) currents. However, in isolated cardiac mitochondria, Glim (10 micromol/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.
Mocanu
M M
MM
Hatter Institute for Cardiovascular Studies, University College London Hospital and Medical School, London, UK.
Maddock
H L
HL
Baxter
G F
GF
Lawrence
C L
CL
Standen
N B
NB
Yellon
D M
DM
D000818:Animals; D003981:Diazoxide / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000150:complications / Q000517:prevention & control*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D051381:Rats; D017207:Rats, Sprague-Dawley; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D016276:Ventricular Function
D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; C117780:mitochondrial K(ATP) channel; C057619:glimepiride; D006160:Guanosine Triphosphate; D003981:Diazoxide; D005905:Glyburide