期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 26, 期 12, 页码 1551-1561出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/sj.jcbfm.9600309
关键词
arachidonic acid; cytochrome P450; hydroxyeicosatetraenoic acid; middle cerebral artery occlusion; N-hydroxy-N-4-butyl-2-methylphenylformamidine; stroke
资金
- NIBIB NIH HHS [EB001975-06] Funding Source: Medline
- NINDS NIH HHS [1R01NS052315-01] Funding Source: Medline
Cytochrome P450 metabolism of arachidonic acid produces the potent vasoconstrictive metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE). Recent studies have implicated 20-HETE as a vasoconstrictive mediator in hemorrhagic stroke. The purpose of this study was to determine the effect of the 20-HETE inhibitor, HET0016, on lesion volume and cerebral blood flow (CBF) after temporary middle cerebral artery occlusion (MCAO) in rats. Plasma pharmacokinetics and tissue concentrations of HET0016 were determined after a 10 mg/kg intraperitoneal dose. Separate rats were treated with HET0016 or vehicle before 90 mins of MCAO. Lesion volume was assessed by 2,3,5-triphenyl-tetrazolium-chloride and cerebral flow was determined using laser Doppler flow. The effect of MCAO on in vitro microsomal formation of mono-oxygenated arachidonic acid metabolites was also determined. Results show that HET0016 has a short biologic half-life, distributes into the brain, and is associated with a 79.6% reduction in 20-HETE concentration in the cortex. Lesion volume was greatly reduced in HET0016-treated (9.1%+/- 4.9%) versus vehicle-treated (57.4%+/- 9.8%; n=6; P < 0.001) rats. An attenuation of the observed decrease in CBF was observed in HET0016-treated (180 mins 89.2%+/- 6.2%; 240 mins 88.1%+/- 5.7% of baseline flow) versus vehicle control (180 mins 57.6%+/- 09.0%; 240 mins 53.8%+/- 20.0% of baseline flow; n=6; P < 0.05). Brain cortical microsomal formation rate of 20-HETE was also reduced at 24 dh in the ipsilateral hemisphere after MCAO. These data support a significant role for 20-HETE in the pathogenesis of ischemic stroke.
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