Abstract |
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%+/-19.0%; 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 h 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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Authors | Samuel M Poloyac, Yuqing Zhang, Robert R Bies, Patrick M Kochanek, Steven H Graham |
Journal | Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
(J Cereb Blood Flow Metab)
Vol. 26
Issue 12
Pg. 1551-61
(Dec 2006)
ISSN: 0271-678X [Print] United States |
PMID | 16570075
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amidines
- HET0016
- Hydroxyeicosatetraenoic Acids
- 20-hydroxy-5,8,11,14-eicosatetraenoic acid
- Cytochrome P-450 Enzyme System
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Topics |
- Amidines
(pharmacokinetics, pharmacology)
- Animals
- Brain Injuries
(metabolism, pathology)
- Brain Ischemia
(metabolism, pathology)
- Cerebrovascular Circulation
(drug effects)
- Cytochrome P-450 Enzyme System
(metabolism)
- Hydroxyeicosatetraenoic Acids
(antagonists & inhibitors, metabolism)
- Male
- Microsomes
(metabolism, pathology)
- Rats
- Rats, Sprague-Dawley
- Reperfusion Injury
(metabolism, pathology)
- Stroke
(metabolism, pathology)
- Vasoconstriction
(drug effects)
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