Oral glyburide, but not glimepiride, blocks the infarct-size limiting effects of pioglitazone.
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.
Ye
Yumei
Y
The Division of Cardiology, University of Texas Medical Branch, 5.106 John Sealy Annex, 301 University Blvd, Galveston, TX 77555-0553, USA.
Lin
Yu
Y
Perez-Polo
Jose R
JR
Birnbaum
Yochai
Y
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000293:injuries; D003627:Data Interpretation, Statistical; D003652:Decanoic Acids / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005905:Glyburide / Q000494:pharmacology* / Q000627:therapeutic use; D006880:Hydroxy Acids / Q000494:pharmacology; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D054086:KATP Channels / Q000037:antagonists & inhibitors; D008026:Ligation / Q000379:methods; D008929:Mitochondria, Heart; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000209:etiology; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D013453:Sulfonylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects
D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C052853:5-hydroxydecanoic acid; C057619:glimepiride; D005905:Glyburide; D000077205:Pioglitazone