title: A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension.
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.
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Rae Bareli 229010, India.
authors.forename: Poorella
authors.initials: P
authors.lastname: Lingeshwar
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Faculty of Pharmacy, Integral University, Lucknow 226001, India.
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Kaur
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Neetu
authors.initials: N
authors.lastname: Singh
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Shubha
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Division of Pharmacokinetics & Metabolism, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Rachumallu
authors.initials: R
authors.lastname: Ramakrishna
authors.affiliation: Division of Pharmacokinetics & Metabolism, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Tulsankar Sachin
authors.initials: TS
authors.lastname: Laxman
authors.affiliation: Division of Pharmacokinetics & Metabolism, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Rabi Sankar
authors.initials: RS
authors.lastname: Bhatta
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Rae Bareli 229010, India.
authors.forename: Hefazat H
authors.initials: HH
authors.lastname: Siddiqui
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Rae Bareli 229010, India; Academy of Scientific and Innovative Research, New Delhi, India. Electronic address: k_hanif@cdri.res.in.
authors.forename: Kashif
authors.initials: K
authors.lastname: Hanif
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000201:enzymology*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D009638:Norepinephrine / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D011014:Pneumonia / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D020888:Vigabatrin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005680:gamma-Aminobutyric Acid; D016686:Monocrotaline; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D010100:Oxygen; D009638:Norepinephrine
keywords: GABA; GABA-T; Nor-epinephrine; Pulmonary hypertension; Right ventricle hypertrophy