Document Detail


Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension.
MedLine Citation:
PMID:  19814724     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is associated with increased contraction and proliferation of pulmonary vascular smooth muscle cells. The anti-diabetic drug metformin has been shown to have relaxant and anti-proliferation properties. We thus examined the effect of metformin in PAH.
EXPERIMENTAL APPROACH: Metformin effects were analysed in hypoxia- and monocrotaline-induced PAH in rats. Ex vivo and in vitro analyses were performed in lungs, pulmonary artery rings and cells.
KEY RESULTS: In hypoxia- and monocrotaline-induced PAH, the changes in mean pulmonary arterial pressure and right heart hypertrophy were nearly normalized by metformin treatment (100 mg.kg(-1).day(-1)). Pulmonary arterial remodelling occurring in both experimental models of PAH was also inhibited by metformin treatment. In rats with monocrotaline-induced PAH, treatment with metformin significantly increased survival. Metformin increased endothelial nitric oxide synthase phosphorylation and decreased Rho kinase activity in pulmonary artery from rats with PAH. These effects are associated with an improvement of carbachol-induced relaxation and reduction of phenylephrine-induced contraction of pulmonary artery. In addition, metformin inhibited mitogen-activated protein kinase activation and strongly reduced pulmonary arterial cell proliferation during PAH. In vitro, metformin directly inhibited pulmonary artery smooth muscle cell growth.
CONCLUSIONS AND IMPLICATIONS: Metformin protected against PAH, regardless of the initiating stimulus. This protective effect may be related to its anti-remodelling property involving improvement of endothelial function, vasodilatory and anti-proliferative actions. As metformin is currently prescribed to treat diabetic patients, assessment of its use as a therapy against PAH in humans should be easier.
Authors:
C Agard; M Rolli-Derkinderen; E Dumas-de-La-Roque; M Rio; C Sagan; J P Savineau; G Loirand; P Pacaud
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-10-08
Journal Detail:
Title:  British journal of pharmacology     Volume:  158     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-28     Completed Date:  2010-02-12     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1285-94     Citation Subset:  IM    
Affiliation:
INSERM, U915, Nantes, France.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Proliferation / drug effects
Chronic Disease
Endothelium, Vascular / drug effects,  metabolism,  physiopathology
Enzyme Activation
Hemodynamics / drug effects
Hypertension, Pulmonary / pathology,  physiopathology,  prevention & control*
Hypertrophy, Right Ventricular / prevention & control
Hypoglycemic Agents / pharmacology*,  therapeutic use
Male
Metformin / pharmacology*,  therapeutic use
Mitogen-Activated Protein Kinases / metabolism
Muscle Contraction / drug effects
Muscle, Smooth, Vascular / drug effects,  pathology,  physiopathology
Nitric Oxide Synthase Type III / metabolism
Phosphorylation
Pulmonary Artery / drug effects,  pathology,  physiopathology
Rats
Rats, Wistar
rho-Associated Kinases / metabolism
Chemical
Reg. No./Substance:
0/Hypoglycemic Agents; 657-24-9/Metformin; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.11.1/rho-Associated Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases
Comments/Corrections

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