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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Zingarelli, B. Szabó, C. Cuzzocrea, S. O'connor, M. Salzman, A. L. |
| Description | Author Affiliation: Cuzzocrea S ( Children's Hospital Medical Center, Division of Critical Care, Cincinnati, Ohio 45229, USA.) |
| Abstract | 1. Peroxynitrite, a cytotoxic oxidant formed from the reaction of nitric oxide (NO) and superoxide is a mediator of cellular injury in ischaemia/reperfusion injury, shock and inflammation. Here we investigated whether L-buthionine-(S,R)-sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase, alters endothelial and vascular smooth muscle injury in response to peroxynitrite in vitro and during endotoxic shock in vivo. 2. In human umbilical vein endothelial cells and in rat aortic smooth muscle cells, BSO (1 mM, for 24 h) enhanced, whereas glutathione (3 mM) or glutathione ethyl ester (3 mM) attenuated the peroxynitrite (100-1000 microM)-induced suppression of mitochondrial respiration (measured by the conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to formazan), formation of nitrotyrosine (detected by Western blotting), protein oxidation (measured by detection of 2,4 dinitrophenylhydrazine-reactive carbonyls), and DNA single strand breakage and activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) (measured by the incorporation of radiolabelled NAD+ into nuclear proteins and by the alkaline unwinding assay, respectively). Glutathione ethyl ester treatment reduced the BSO-induced enhancement of peroxynitrite-induced cytotoxicity. 3. In rat isolated thoracic aortic rings, BSO treatment (in vivo, at 1 g kg(-1) intraperitoneally (i.p.) for 24 h) enhanced, whereas pretreatment with glutathione (in vitro, 3 mM) attenuated the peroxynitrite-induced reduction of the contractions to noradrenaline, and the peroxynitrite-induced impairment of the endothelium-dependent relaxations to acetylcholine. 4. In BSO-pretreated rats, treatment with bacterial lipopolysaccharide (LPS, 15 mg kg(-1), i.p., for 6 h) caused a more pronounced vascular hyporeactivity and endothelial dysfunction ex vivo. BSO pretreatment also increased the degree of nitrotyrosine staining (detected by imunohistochemistry) in the aorta after LPS treatment. 5. In conclusion, our results demonstrate that L-buthionine-(S,R)-sulphoximine, an inhibitor of gamma-glutamylcysteine synthetase enhances peroxynitrite- and endotoxic shock-induced vascular failure. Based on these findings, we suggest that endogenous glutathione plays an important protective role against peroxynitrite- and LPS-induced vascular injury. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 3 |
| Volume Number | 123 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 1998-02-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Buthionine Sulfoximine Pharmacology Endothelium, Vascular Drug Effects Enzyme Inhibitors Glutamate-Cysteine Ligase Antagonists & Inhibitors Nitrates Shock, Septic Physiopathology Animals Aorta, Thoracic Physiology Cell Survival Cells, Cultured Cytology Enzyme Induction Glutathione In Vitro Techniques Muscle Contraction Nitric Oxide Synthase Biosynthesis Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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