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.
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.
Iwasa
Masamitsu
M
Department of Cardiology, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan.
Kobayashi
Hiroyuki
H
Yasuda
Shinji
S
Kawamura
Itta
I
Sumi
Shohei
S
Yamada
Yoshihisa
Y
Shiraki
Takeru
T
Yamaki
Takahiko
T
Ushikoshi
Hiroaki
H
Aoyama
Takuma
T
Nishigaki
Kazuhiko
K
Takemura
Genzou
G
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
Minatoguchi
Shinya
S
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
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