title: Antidiabetic drug voglibose is protective against ischemia-reperfusion injury through glucagon-like peptide 1 receptors and the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathway in rabbits.
abstract: Glucagon-like peptide 1 (GLP-1) reportedly exerts a protective effect against cardiac ischemia. We hypothesized that the alpha-glucosidase inhibitor voglibose, an unabsorbable antidiabetic drug with cardioprotective effects, may act through stimulation of GLP-1 receptors. The results of the present study suggest oral administration of voglibose reduces myocardial infarct size and mitigates cardiac dysfunction in rabbits after 30 minutes of coronary occlusion and 48 hours of reperfusion. Voglibose increased basal and postprandial plasma GLP-1 levels and reduced postprandial plasma glucose levels. The infarct size-reducing effect of voglibose was abolished by treatment with exendin(9-39), wortmannin, Nomega-nitro-L-arginine methylester, or 5-hydroxydecanoate), which inhibit GLP-1 receptors, phosphoinositide 3-kinase, nitric oxide synthase, and K(ATP) channels, respectively. Western blot analysis showed that treatment with voglibose upregulated myocardial levels of phospho-Akt, phosphoendothelial nitric oxide synthase after myocardial infarction. The upregulation of phospho-Akt was inhibited by exendin(9-39) and wortmannin. These findings suggest that voglibose reduces myocardial infarct size through stimulation of GLP-1 receptors, activation of the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathways, and the opening of mitochondrial K(ATP) channels. These findings may provide new insight into therapeutic strategies for the treatment of patients with coronary artery disease.
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Iwasa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuda
authors.forename: Itta
authors.initials: I
authors.lastname: Kawamura
authors.forename: Shohei
authors.initials: S
authors.lastname: Sumi
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamada
authors.forename: Takeru
authors.initials: T
authors.lastname: Shiraki
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ushikoshi
authors.forename: Takuma
authors.initials: T
authors.lastname: Aoyama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishigaki
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology; D003652:Decanoic Acids; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006880:Hydroxy Acids; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007294:Inositol / Q000031:analogs & derivatives; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III; D010770:Phosphotransferases / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011817:Rabbits; D018027:Receptors, Glucagon; D015427:Reperfusion Injury / Q000378:metabolism*; D000520:alpha-Glucosidases / Q000378:metabolism / Q000494:pharmacology
chemical_list: D003652:Decanoic Acids; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D006880:Hydroxy Acids; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D007294:Inositol; C052853:5-hydroxydecanoic acid; D052216:Glucagon-Like Peptide 1; D001120:Arginine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D010770:Phosphotransferases; D051057:Proto-Oncogene Proteins c-akt; D000520:alpha-Glucosidases; C102817:voglibose