The Journal of pharmacology and experimental therapeutics, 2001-09, Vol.298 (3), p.879
2001
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Details
- Autor(en) / Beteiligte
- Titel
- Oxidative inactivation of nitric oxide and endothelial dysfunction in stroke-prone spontaneous hypertensive rats
- Ist Teil von
- The Journal of pharmacology and experimental therapeutics, 2001-09, Vol.298 (3), p.879
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2001
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- This study tested the hypothesis that increased nitric oxide (NO) inactivation and concurrent peroxynitrite formation is responsible for endothelial dysfunction in the spontaneously hypertensive stroke-prone rat (SHRSP). In SHRSP, the aortic vasorelaxation to acetylcholine (ACh) was decreased (p < 0.05), but NO production was unchanged. Nitrotyrosine staining, a footprint of peroxynitrite (ONOO(-)) formation, was detected. Exposure of SHRSP to a high-salt, high-fat diet (SFD) further exacerbated hypertension and accelerated end-organ disease. A severe endothelial dysfunction [maximal ACh relaxation: 49.8 +/- 2.1 versus 94.5 +/- 1.8% in Wistar-Kyoto rats (WKY), p < 0.01], increased basal NO production (482 +/- 17 versus 356 +/- 21 nM, p < 0.01), decreased ACh-stimulated NO production (57 +/- 6 versus 112 +/- 6 nM, p < 0.01), extensive inducible NO synthase and nitrotyrosine staining, elevated nitrotyrosine content (21-fold increase over WKY), and a high percentage of cells with DNA damage were observed in the aortic tissues from these animals. Treatment of SHRSP on SFD with carvedilol restored ACh-induced vasorelaxation and NO production, inhibited nitrotyrosine formation, reduced vascular cell DNA damage, and reduced end-organ injury. These data demonstrate that endothelial dysfunction was caused by increased NO inactivation alone (SHRSP) or in combination with decreased NO production from endothelial NO synthase (SHRSP on SFD). Antioxidant treatment with carvedilol exerted significant vascular protective effects, attenuated end-organ damage, and decreased mortality under these conditions.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-3565Titel-ID: cdi_pubmed_primary_11504780
- Format
- –
- Schlagworte
- Acetylcholine - pharmacology, Adrenergic beta-Antagonists - pharmacology, Animals, Aorta, Thoracic - drug effects, Aorta, Thoracic - metabolism, Apoptosis - drug effects, Blood Pressure - drug effects, Carbazoles - pharmacology, Endothelium, Vascular - metabolism, Immunohistochemistry, In Situ Nick-End Labeling, Male, Muscle Relaxation - drug effects, Muscle, Smooth, Vascular - drug effects, Muscle, Smooth, Vascular - metabolism, Nitric Oxide - blood, Nitric Oxide - metabolism, Nitric Oxide Synthase - biosynthesis, Nitric Oxide Synthase Type II, Oxidation-Reduction, Propanolamines - pharmacology, Rats, Rats, Inbred SHR, Stroke - genetics, Stroke - metabolism, Stroke - mortality, Tyrosine - analogs & derivatives, Tyrosine - metabolism