| Nifedipine prevents vascular endothelial dysfunction in a mouse model of obesity and type 2 diabetes, by improving eNOS dysfunction and dephosphorylation. | |
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MedLine Citation:
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PMID: 21059340 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The effect of calcium channel blockers (CCBs) on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of nifedipine, a dihydropyridine CCB, on obesity, glucose intolerance and vascular endothelial dysfunction in db/db mice (a mouse model of obesity and type 2 diabetes). db/db mice, fed high-fat diet (HFD) were treated with vehicle, nifedipine (10 mg kg(-1) day(-1)) or hydralazine (5 mg kg(-1) day(-1)) for 4 weeks, and the protective effects were compared. Although nifedipine and hydralazine exerted similar blood pressure lowering in db/db mice, neither affected body weight, fat weight, and glucose intolerance of db/db mice. However, nifedipine, but not hydralazine, significantly improved vascular endothelial function in db/db mice, being accompanied by more attenuation of vascular superoxide by nifedipine than hydralazine. These protective effects of nifedipine were attributed to the attenuation of eNOS uncoupling as shown by the prevention of vascular endothelial nitric oxide synthase (eNOS) dimer disruption, and the prevention of dihydrofolate reductase (DHFR) downregulation, the key enzyme responsible for eNOS uncoupling. Moreover, nifedipine, but not hydralazine, significantly prevented the decreases in phosphorylation of vascular akt and eNOS in db/db mice. Our work provided the first evidence that nifedipine prevents vascular endothelial dysfunction, through the inhibition of eNOS uncoupling and the enhancement of eNOS phosphorylation, independently of blood pressure-lowering effect. We propose that nifedipine may be a promising therapeutic agent for cardiovascular complications in type 2 diabetes. |
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Authors:
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Eiichiro Yamamoto; Taishi Nakamura; Keiichiro Kataoka; Yoshiko Tokutomi; Yi-Fei Dong; Masaya Fukuda; Hisato Nako; Osamu Yasuda; Hisao Ogawa; Shokei Kim-Mitsuyama |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-06 |
Journal Detail:
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Title: Biochemical and biophysical research communications Volume: 403 ISSN: 1090-2104 ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-20 Completed Date: 2011-01-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372516 Medline TA: Biochem Biophys Res Commun Country: United States |
Other Details:
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Languages: eng Pagination: 258-63 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood Pressure / drug effects Body Weight / drug effects Calcium Channel Blockers / pharmacology* Diabetes Mellitus, Experimental / enzymology* Diabetes Mellitus, Type 2 / enzymology* Disease Models, Animal Endothelium, Vascular / drug effects*, enzymology, physiopathology Glucose Tolerance Test Mice Mice, Inbred Strains Nifedipine / pharmacology* Nitric Oxide Synthase Type III / metabolism* Obesity / enzymology* Organ Size / drug effects Phosphorylation Proto-Oncogene Proteins c-akt / metabolism Superoxides / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Calcium Channel Blockers; 11062-77-4/Superoxides; 21829-25-4/Nifedipine; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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