Oral glyburide, but not glimepiride, blocks the infarct-size limiting effects of pioglitazone

Yumei Ye, Yu Lin, Jose R. Perez-Polo, Yochai Birnbaum

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background: Many patients with type 2 diabetes mellitus receive several oral hypoglycemic agents, including sulfonylurea drugs. Intravenous glyburide (Glyb), a sulfonylurea agent, blocks the protective effects of "ischemic" and pharmacologic preconditioning in various animal models without affecting myocardial infarct size when administered alone. However, there are conflicting results when other sulfonylurea drugs are used. Pioglitazone (PIO) reduces infarct size in the rat. We asked whether oral Glyb and glimepiride (Glim) affect the infarct size-limiting effects of PIO. Methods: Sprague-Dawley rats received 3-day oral treatment with: PIO (5 mg/kg/day); PIO+Glyb (10 mg/kg/day); PIO+Glim (4 mg/kg/day) or water alone (experiment 1) or PIO (5 mg/kg/day) with or without 5-hydroxydecanoate (5HD, 10 mg/kg), a specific mitochondrial ATP-sensitive K+ channels inhibitor, administered intravenously 30 min before coronary artery ligation. PIO, Glyb and Glim were administered by oral gavage. Sugar 5% was added to water to prevent hypoglycemia. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (n=6 in each group). Ischemic area at risk was assessed by blue dye and infarct size by triphenyl-tetrazolium-chloride. Results: Body weight and the size of the area at risk were comparable among groups. Infarct size (% of the area at risk) was significantly smaller in the PIO (14.3±1.1%; p<0.001) and PIO+Glim (13.2±0.8%; p<0.001) groups than in the control group (37.7±1.2%). Glyb completely blocked the effect of PIO (43.0±1.7%; p<0.001). Glim did not affect the protective effect of PIO (p=0.993). 5HD blocked the protective effect of PIO (infarct size 48.5±0.8% versus 14.8±0.6%, respectively; p<0.0001). In conclusion, the infarct size limiting effects of PIO are dependent on activation of mitochondrial ATP-sensitive K+ channels. Oral Glyb, but not Glim, blocks the infarct size limiting effects of PIO. It is plausible that Glyb affects other pleiotropic effects of PIO and thus may attenuate favorable effects on cardiovascular outcomes. In contrast, Glim does not attenuate the protective effect of PIO.

Original languageEnglish (US)
Pages (from-to)429-436
Number of pages8
JournalCardiovascular Drugs and Therapy
Volume22
Issue number6
DOIs
StatePublished - Dec 2008

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pioglitazone
glimepiride
Glyburide

Keywords

  • Diabetes mellitus
  • Infarct size
  • Pioglitazone
  • Preconditioning
  • Sulfonylurea

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Oral glyburide, but not glimepiride, blocks the infarct-size limiting effects of pioglitazone. / Ye, Yumei; Lin, Yu; Perez-Polo, Jose R.; Birnbaum, Yochai.

In: Cardiovascular Drugs and Therapy, Vol. 22, No. 6, 12.2008, p. 429-436.

Research output: Contribution to journalArticle

Ye, Yumei ; Lin, Yu ; Perez-Polo, Jose R. ; Birnbaum, Yochai. / Oral glyburide, but not glimepiride, blocks the infarct-size limiting effects of pioglitazone. In: Cardiovascular Drugs and Therapy. 2008 ; Vol. 22, No. 6. pp. 429-436.
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AU - Ye, Yumei

AU - Lin, Yu

AU - Perez-Polo, Jose R.

AU - Birnbaum, Yochai

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N2 - Background: Many patients with type 2 diabetes mellitus receive several oral hypoglycemic agents, including sulfonylurea drugs. Intravenous glyburide (Glyb), a sulfonylurea agent, blocks the protective effects of "ischemic" and pharmacologic preconditioning in various animal models without affecting myocardial infarct size when administered alone. However, there are conflicting results when other sulfonylurea drugs are used. Pioglitazone (PIO) reduces infarct size in the rat. We asked whether oral Glyb and glimepiride (Glim) affect the infarct size-limiting effects of PIO. Methods: Sprague-Dawley rats received 3-day oral treatment with: PIO (5 mg/kg/day); PIO+Glyb (10 mg/kg/day); PIO+Glim (4 mg/kg/day) or water alone (experiment 1) or PIO (5 mg/kg/day) with or without 5-hydroxydecanoate (5HD, 10 mg/kg), a specific mitochondrial ATP-sensitive K+ channels inhibitor, administered intravenously 30 min before coronary artery ligation. PIO, Glyb and Glim were administered by oral gavage. Sugar 5% was added to water to prevent hypoglycemia. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (n=6 in each group). Ischemic area at risk was assessed by blue dye and infarct size by triphenyl-tetrazolium-chloride. Results: Body weight and the size of the area at risk were comparable among groups. Infarct size (% of the area at risk) was significantly smaller in the PIO (14.3±1.1%; p<0.001) and PIO+Glim (13.2±0.8%; p<0.001) groups than in the control group (37.7±1.2%). Glyb completely blocked the effect of PIO (43.0±1.7%; p<0.001). Glim did not affect the protective effect of PIO (p=0.993). 5HD blocked the protective effect of PIO (infarct size 48.5±0.8% versus 14.8±0.6%, respectively; p<0.0001). In conclusion, the infarct size limiting effects of PIO are dependent on activation of mitochondrial ATP-sensitive K+ channels. Oral Glyb, but not Glim, blocks the infarct size limiting effects of PIO. It is plausible that Glyb affects other pleiotropic effects of PIO and thus may attenuate favorable effects on cardiovascular outcomes. In contrast, Glim does not attenuate the protective effect of PIO.

AB - Background: Many patients with type 2 diabetes mellitus receive several oral hypoglycemic agents, including sulfonylurea drugs. Intravenous glyburide (Glyb), a sulfonylurea agent, blocks the protective effects of "ischemic" and pharmacologic preconditioning in various animal models without affecting myocardial infarct size when administered alone. However, there are conflicting results when other sulfonylurea drugs are used. Pioglitazone (PIO) reduces infarct size in the rat. We asked whether oral Glyb and glimepiride (Glim) affect the infarct size-limiting effects of PIO. Methods: Sprague-Dawley rats received 3-day oral treatment with: PIO (5 mg/kg/day); PIO+Glyb (10 mg/kg/day); PIO+Glim (4 mg/kg/day) or water alone (experiment 1) or PIO (5 mg/kg/day) with or without 5-hydroxydecanoate (5HD, 10 mg/kg), a specific mitochondrial ATP-sensitive K+ channels inhibitor, administered intravenously 30 min before coronary artery ligation. PIO, Glyb and Glim were administered by oral gavage. Sugar 5% was added to water to prevent hypoglycemia. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (n=6 in each group). Ischemic area at risk was assessed by blue dye and infarct size by triphenyl-tetrazolium-chloride. Results: Body weight and the size of the area at risk were comparable among groups. Infarct size (% of the area at risk) was significantly smaller in the PIO (14.3±1.1%; p<0.001) and PIO+Glim (13.2±0.8%; p<0.001) groups than in the control group (37.7±1.2%). Glyb completely blocked the effect of PIO (43.0±1.7%; p<0.001). Glim did not affect the protective effect of PIO (p=0.993). 5HD blocked the protective effect of PIO (infarct size 48.5±0.8% versus 14.8±0.6%, respectively; p<0.0001). In conclusion, the infarct size limiting effects of PIO are dependent on activation of mitochondrial ATP-sensitive K+ channels. Oral Glyb, but not Glim, blocks the infarct size limiting effects of PIO. It is plausible that Glyb affects other pleiotropic effects of PIO and thus may attenuate favorable effects on cardiovascular outcomes. In contrast, Glim does not attenuate the protective effect of PIO.

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KW - Pioglitazone

KW - Preconditioning

KW - Sulfonylurea

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