Both stimulation of GLP‐1 receptors and inhibition of glycogenolysis additively contribute to a protective effect of oral miglitol against ischaemia‐reperfusion injury in rabbits

• Published in: British journal of pharmacology Vol. 164; no. 1; pp. 119 - 131
• Main Authors: Iwasa, Masamitsu, Yamada, Yoshihisa, Kobayashi, Hiroyuki, Yasuda, Shinji, Kawamura, Itta, Sumi, Shohei, Shiraki, Takeru, Yamaki, Takahiko, Ushikoshi, Hiroaki, Hattori, Arihiro, Aoyama, Takuma, Nishigaki, Kazuhiko, Takemura, Genzou, Fujiwara, Hisayoshi, Minatoguchi, Shinya
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2011; Nature Publishing Group
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - blood; 1-Deoxynojirimycin - pharmacology; Administration, Oral; Akt; Animals; Biological and medical sciences; Blood Glucose - drug effects; Blood Pressure - drug effects; Cardiology. Vascular system; Coronary heart disease; Drug Synergism; GLP‐1 receptor; Glucagon-Like Peptide 1 - blood; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor; Glycogenolysis - drug effects; Heart; Heart - drug effects; Heart Rate - drug effects; Hypoglycemic Agents - blood; Hypoglycemic Agents - pharmacology; Insulin - blood; Male; Medical sciences; miglitol; myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - prevention & control; Myocarditis. Cardiomyopathies; Myocardium - metabolism; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; PI3‐kinase; plasma GLP‐1 level; Proto-Oncogene Proteins c-akt - metabolism; Rabbits; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - metabolism; Research Papers; Myocardial infarction; Biological fluid; GLP-1 receptor; Rabbit; Cardiovascular disease; Stimulation; Myocardial disease; Blood plasma; Prevention; Hypoglycemic agent; Gastrointestinal hormone; Glycogenolysis; Enzyme; Transferases; Ischemia reperfusion; Miglitol; Oral administration; Enzyme inhibitor; Akt protein kinase; plasma GLP-1 level; Akt; PI3-kinase; Lagomorpha; Coronary heart disease; Glucagon like peptide 1; Glycosylases; Vertebrata; Mammalia; α-Glucosidase; Kinase; Glycosidases; Animal; Hydrolases; Lesion
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01357.x

BACKGROUND AND PURPOSE We previously reported that pre‐ischaemic i.v. miglitol reduces myocardial infarct size through the inhibition of glycogenolysis during ischaemia. Oral administration of miglitol has been reported to produce glucagon‐like peptide 1 (GLP‐1). We hypothesized that p.o. administration of miglitol, an absorbable antidiabetic drug, reduces myocardial infarct size by stimulating GLP‐1 receptors and inhibiting glycogenolysis in the myocardium. EXPERIMENTAL APPROACH The effects of p.o. and i.v. administration of miglitol on myocardial infarct size were compared in a rabbit model of ischaemia induced by 30 min of coronary occlusion and 48 h of reperfusion. The levels of phospho(p)‐PI3kinase and p‐Akt were measured in cardiac tissue by use of Western blot analysis. RESULTS Both p.o. and i.v. administration of miglitol reduced the infarct size, and this effect was greater after p.o. than after i.v. administration under similar plasma miglitol concentrations. The reduction in infarct size induced by p.o. miglitol but not that induced by i.v. miglitol was partially inhibited by treatment with exendin(9‐39), a GLP‐1 receptor blocker. Both p.o. and i.v. miglitol improved ejection fraction and ±dP/dt after myocardial infarction. Miglitol administered p.o. but not i.v. up‐regulated the myocardial expression of phospho(p)‐PI3kinase and p‐Akt following myocardial infarction; an effect that was inhibited by exendin(9‐39). CONCLUSIONS AND IMPLICATIONS Administration of miglitol p.o. reduces myocardial infarct size through stimulation of GLP‐1 receptors and activation of PI3kinase‐Akt pathway in addition to the inhibition of glycogenolysis. These findings may have clinical implications for the p.o. administration of miglitol for the treatment of patients with diabetes mellitus combined with coronary artery disease.