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A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension.

TitleA study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension.
Publication TypeJournal Article
Year of Publication2016
AuthorsLingeshwar P, Kaur G, Singh N, Singh S, Mishra A, Shukla S, Ramakrishna R, Laxman TSachin, Bhatta RSankar, Siddiqui HH, Hanif K
JournalPulm Pharmacol Ther
Volume36
Pagination10-21
Date Published2016 Feb
ISSN1522-9629
Keywords4-Aminobutyrate Transaminase, Animals, Enzyme Inhibitors, gamma-Aminobutyric Acid, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Lung, Male, Monocrotaline, Norepinephrine, Oxidative Stress, Oxygen, Pneumonia, Rats, Rats, Sprague-Dawley, Survival Analysis, Vigabatrin
Abstract

Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of γ-Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE. The effect of daily oral administration of GABA-T inhibitor, Vigabatrin (GVG, 50 and 75 mg/kg/day, 35 days) was studied following a single subcutaneous administration of monocrotaline (MCT, 60 mg/kg) in male SD rats. The pressure and hypertrophy of right ventricle (RV), oxidative stress, inflammation, pulmonary vascular remodelling were assessed after 35 days in MCT treated rats. The expression of GABA-T and HIF-1α was studied in lung tissue. The levels of plasma NE (by High performance liquid chromatography coupled with electrochemical detector; HPLC-ECD) and lung GABA (by liquid chromatography-mass spectrometry) were also estimated. GVG at both doses significantly attenuated increased in pressure (35.82 ± 4.80 mm Hg, p < 0.001; 28.37 ± 3.32 mm Hg, p < 0.001 respectively) and hypertrophy of RV, pulmonary vascular remodelling, oxidative stress and inflammation in lungs of MCT exposed rats. GVG also reduced the expression of GABA-T and HIF-1α in MCT treated rats. Increased NE level and decreased GABA level was also reversed by GVG in MCT exposed rats. GABA-T plays an important role in PH by modulating SNS activity and may be considered as a therapeutic target in PH.

DOI10.1016/j.pupt.2015.11.002
Alternate JournalPulm Pharmacol Ther
PubMed ID26608704