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Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension
Author(s) -
Agard C,
RolliDerkinderen M,
DumasdeLaRoque E,
Rio M,
Sagan C,
Savineau JP,
Loirand G,
Pacaud P
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00445.x
Subject(s) - metformin , medicine , pulmonary artery , pulmonary hypertension , hypoxia (environmental) , pharmacology , nitric oxide , vasodilation , contraction (grammar) , vascular smooth muscle , vascular remodelling in the embryo , endocrinology , diabetes mellitus , chemistry , smooth muscle , organic chemistry , oxygen
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.