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Treatment with the cytochrome P450 ω-hydroxylase inhibitor HET0016 attenuates cerebrovascular inflammation, oxidative stress and improves vasomotor function in spontaneously hypertensive rats.
MedLine Citation:
PMID:  23194285     Owner:  NLM     Status:  Publisher    
BACKGROUND AND PURPOSE: Hypertension increases cerebrovascular oxidative stress and inflammation and impairs vasomotor function. These pathological alterations lead to dysregulation of cerebral blood flow and exacerbate atherogenesis, increasing the morbidity of ischemic cerebrovascular diseases and promoting vascular cognitive impairment. We aimed to test the hypothesis that increased production of the arachidonic acid metabolite 20-HETE contributes to hypertension-induced cerebrovascular alterations. EXPERIMENTAL APPROACH: We treated male spontaneously hypertensive rats (SHR) with HET0016 (N-Hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine), an inhibitor of 20-HETE synthesis. In middle cerebral arteries (MCAs) of SHRs we focused on vasomotor responses and endpoints that are highly relevant for cellular ROS production, inflammatory cytokine expression and NF-κB activation. KEY RESULTS: SHRs treated with HET0016 remained hypertensive (SHR+HET0016: 149±8 mmHg, WKY: 115±4 mmHg; p<0.05.), although their systolic blood pressure was decreased compared to untreated SHRs (191±6 mmHg). In MCAs of SHRs flow-induced constriction was increased, whereas acetylcholine- and ATP-induced dilations were impaired. This functional impairment was reversed by treatment with HET0016. Treatment with HET0016 also significantly decreased oxidative stress in MCAs of SHRs (as shown by DHE staining and analysis of vascular 5-nitrotyrosine, 4-hydroxynonenal and carbonyl content) and inhibited cerebrovascular inflammation (shown by the reduced mRNA expression of TNFα, IL-1β and IL-6). Treatment of SHRs with HET0016 also attenuated vascular NF-κB activation. In vitro treatment with 20-HETE significantly increased vascular production of reactive oxygen species and promoted NF-κB activation in cultured cerebromicrovascular endothelial cells. CONCLUSIONS AND IMPLICATIONS: Taken together, treatment with HET0016 confers anti-oxidative and anti-inflammatory effects in the cerebral arteries of SHRs by disrupting 20-HETE mediated autocrine/paracrine signaling pathways in the vascular wall. It is likely that HET0016-induced decreases in blood pressure also potentiate the cerebrovascular protective effects of the drug.
Peter Toth; Anna Csiszar; Danuta Sosnowska; Zsuzsanna Tucsek; Peter Cseplo; Zsolt Springo; Stefano Tarantini; William E Sonntag; Zoltan Ungvari; Akos Koller
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-30
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma, Health Sciences Center, OK, USA; Department of Pathophysiology and Gerontology, Medical School, University of Pecs, Pecs, Hungary.
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