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

M.M. Mocanu, H.L. Maddock, G.F. Baxter, C.L. Lawrence, Nicholas B. Standen, D.M. Yellon

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

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 2× 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.
Original languageEnglish
Pages (from-to)3111-3116
Number of pages6
JournalCirculation
Volume103
Issue number25
DOIs
Publication statusPublished - 26 Jun 2001
Externally publishedYes

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Keywords

  • potassium
  • myocardial infarction
  • diabetes mellitus
  • ion channels

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