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Electrophysiological and contractile effects of cardiac glutathione depletion: relation to myocyte reactive nitrogen species and NOS2 induction
Author(s) -
Han Bing,
Huang Hong,
Joshi Mandar S,
Schanbacher Brandon L,
Bauer John A
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a801-a
Subject(s) - glutathione , oxidative stress , myocyte , medicine , chemistry , buthionine sulfoximine , endocrinology , nitrotyrosine , pharmacology , biochemistry , nitric oxide , nitric oxide synthase , enzyme
Oxidative stress has been linked to ischemic heart disease. Its role in non‐ischemic settings is less established. Recycling of glutathione (GSH) with its disulfide product (GSSG) is a major component of intracellular redox regulation. We tested the hypothesis that in vivo cardiac GSH depletion in mice causes increased myocyte oxidative stress and modulates cardiac performance. Mice were pretreated with buthionine sulfoximine (BSO, 888mg/kg, glutathione biosynthesis inhibitor); cardiac performance was measured at 24hr using ECGs and echocardiography, at rest and after isoproterenol dosing (ISO, 2.5mg/kg ip). LV tissues were isolated for GSH and GSSG determination followed by NOS2 and protein 3‐nitrotyrosine prevalence by histochemistry. BSO caused reductions of GSH and GSH/GSSG at 24hr (p<0.01), returning to control levels by 7d. At rest, GSH depletion caused elongation of QTc, decreased LV diastolic performance, and increased LV stroke volume (p<0.05). ISO caused increases in QTc and provoked arrhythmia in BSO pretreated animals only. GSH depletion was correlated with increased myocyte NOS2 and protein 3‐NT, as well as QTc (p<0.01). These data demonstrate that acute depletion of cardiac GSH can perturb myocardial performance. These perturbations are enhanced during stress and may be mediated by myocyte NOS2 induction and nitration of cellular constituents.