Document Detail


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.
MedLine Citation:
PMID:  21426318     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Masamitsu Iwasa; Yoshihisa Yamada; Hiroyuki Kobayashi; Shinji Yasuda; Itta Kawamura; Shohei Sumi; Takeru Shiraki; Takahiko Yamaki; Hiroaki Ushikoshi; Arihiro Hattori; Takuma Aoyama; Kazuhiko Nishigaki; Genzou Takemura; Hisayoshi Fujiwara; Shinya Minatoguchi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  164     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-08     Completed Date:  2012-02-02     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  119-31     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Affiliation:
Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
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MeSH Terms
Descriptor/Qualifier:
1-Deoxynojirimycin / analogs & derivatives*,  blood,  pharmacology
Administration, Oral
Animals
Blood Glucose / drug effects
Blood Pressure / drug effects
Drug Synergism
Glucagon-Like Peptide 1 / blood,  metabolism
Glycogenolysis / drug effects*
Heart / drug effects*
Heart Rate / drug effects
Hypoglycemic Agents / blood,  pharmacology
Insulin / blood
Male
Myocardial Infarction / drug therapy,  metabolism
Myocardial Reperfusion Injury / metabolism*,  prevention & control*
Myocardium / metabolism*
Peptide Fragments / pharmacology
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Rabbits
Receptors, Glucagon / antagonists & inhibitors,  metabolism*
Chemical
Reg. No./Substance:
0/Blood Glucose; 0/Hypoglycemic Agents; 0/Insulin; 0/Peptide Fragments; 0/Receptors, Glucagon; 0/glucagon-like peptide-1 receptor; 133514-43-9/exendin (9-39); 19130-96-2/1-Deoxynojirimycin; 72432-03-2/miglitol; 89750-14-1/Glucagon-Like Peptide 1; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections
Erratum In:
Br J Pharmacol. 2012 Jul;166(5):1744

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