20-HETE contributes to the acute fall in cerebral blood  flow after subarachnoid hemorrhage in the rat

Kehl, Franz; Cambj-Sapunar, Liana; Maier, Kristopher G.; Miyata, Noriyuki; Kametani, Shunishi; Okamoto, Hirotsugu; Hudetz, Anthony G.; Schulte, Marie L.; Zagorac, Drazen; Harder, David R.; Roman, Richard J.

doi:10.1152/ajpheart.00924.2001

Cited by 97 publications

(95 citation statements)

References 43 publications

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“…We selected a dose of 10 mg/kg administered intraperitoneally, which produced 1 h concentrations (Kehl et al, 2002). However, the brain concentrations reported in the study by Kehl et al were 7.2 mmol/L as compared with 0.2 mmol/L reported in the present study.…”

Section: Discussioncontrasting

confidence: 61%

Protective Effect of the 20-HETE Inhibitor HET0016 on Brain Damage after Temporary Focal Ischemia

Poloyac

Zhang

Bies

et al. 2006

J Cereb Blood Flow Metab

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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%64.9%) versus vehicle-treated (57.4%69.8%; n = 6; P < 0.001) rats. An attenuation of the observed decrease in CBF was observed in HET0016-treated (180 mins 89.2%66.2%; 240 mins 88.1%65.7% of baseline flow) versus vehicle control (180 mins 57.6%619.0%; 240 mins 53.8%620.0% 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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Section: Discussioncontrasting

confidence: 61%

Protective Effect of the 20-HETE Inhibitor HET0016 on Brain Damage after Temporary Focal Ischemia

Poloyac

Zhang

Bies

et al. 2006

J Cereb Blood Flow Metab

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“…An increase in 20-HETE has been documented to be associated with exacerbation of MI and stroke in multiple animal models, and inhibition of the production of 20-HETE decreases the infarct size and ablates strokes in several animal models (34)(35)(36)(37). To study the mechanism by which 20-HETE enhances the speed of blood clotting, we measured the function of coagulation and platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events

Liu

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

102

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Chronic administration of high levels of selective COX-2 inhibitors (coxibs), particularly rofecoxib, valdecoxib, and parecoxib, increases risk for cardiovascular disease. Understanding the possibly multiple mechanisms underlying these adverse cardiovascular events is critical for evaluating the risks and benefits of coxibs and for development of safer coxibs. The current understanding of these mechanisms is likely incomplete. Using a metabolomics approach, we demonstrate that oral administration of rofecoxib for 3 mo results in a greater than 120-fold higher blood level of 20-hydroxyeicosatetraenoic acid (20-HETE), which correlates with a significantly shorter tail bleeding time in a murine model. We tested the hypothesis that this dramatic increase in 20-HETE is attributable to inhibition of its metabolism and that the shortened bleeding time following rofecoxib administration is attributable, in part, to this increase. The s.c. infusion of 20-HETE shortened the tail bleeding time dramatically. Neither 20-HETE biosynthesis nor cytochrome P4A-like immune reactivity was increased by rofecoxib administration, but 20-HETE production increased in vitro with the addition of coxib. 20-HETE is significantly more potent than its COX-mediated metabolites in shortening clotting time in vitro. Furthermore, 20-HETE but not rofecoxib significantly increases rat platelet aggregation in vitro in a dose-dependent manner. These data suggest 20-HETE as a marker of rofecoxib exposure and that inhibition of 20-HETE's degradation by rofecoxib is a partial explanation for its dramatic increase, the shortened bleeding time, and, possibly, the adverse cardiovascular events associated with rofecoxib. cardiovascular side effect | coxib | eicosanoids | metabolomics | Vioxx

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“…Recent studies have indicated that the levels of 20-HETE increase in the CSF of rats (Kehl et al, 2002;Cambj-Sapunar et al, 2003), dogs (Hacein-Bey et al, 2004a), and man (Hacein-Bey et al, 2004b) following SAH and inhibition of the synthesis of 20-HETE, with 17-ODYA or HET0016 (Kehl et al, 2002;Cambj-Sapunar et al, 2003), or blockade of its vasoconstrictor actions with WIT0002 (Yu et al, 2004) can prevent the acute fall in CBF. There is also evidence that blockade of the synthesis of 20-HETE can even reverse delayed vasospasm in dogs subjected to the dual hemorrhage model (Hacein-Bey et al, 2004a).…”

Section: Discussionmentioning

confidence: 99%

“…and thiobutabarbital (Inactin; 50 mg/kg i.p.) and surgically prepared for induction of SAH and measurement of CBF through an intact cranial window as previously described (Kehl et al, 2002;Cambj-Sapunar et al, 2003). The head of the rat was placed in a stereotaxic apparatus and the atlantooccipital membrane was exposed by separating the muscle layers at the base of the skull.…”

Section: Effects Of Pretreatment Of Rats With Ts-011 On the Acute Falmentioning

confidence: 99%

“…In this regard, 20-HETE is a potent constrictor of cerebral arteries (Gebremedhin et al, 1998(Gebremedhin et al, , 2000, and the levels of 20-HETE increase in CSF following SAH (Kehl et al, 2002;CambjSapunar et al, 2003). Inhibition of the synthesis of 20-HETE, with 17-octadecynoic acid (17-ODYA) or HET0016, or blockade of its vasoconstrictor actions with WIT0002 prevents the acute fall in cerebral flow following SAH (Kehl et al, 2002;Yu et al, 2004). There is also evidence that blockade of the synthesis of 20-HETE may also reverse delayed vasospasm in dogs (Hacein-Bey et al, 2004a).…”

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confidence: 99%

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Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Miyata

Seki²,

Tanaka³

et al. 2005

J Pharmacol Exp Ther

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The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-NЈ-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC 50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC 50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 M. TS-011 (0.01-1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.Each year, 750,000 strokes occur in the United States. Approximately 80% of the strokes are ischemic, and 20% are hemorrhagic. Hemorrhagic stroke commonly occurs after rupture of aneurysms or head trauma. There is an initial period of cerebral ischemia lasting several hours due to a rise in cerebral spinal fluid (CSF) pressure and acute cerebral vasospasm. One-half of the patients that survive later develop delayed vasospasm. The mortality in the 1st month hovers around 50%. The majority of deaths (Ͼ60%) occur during the first 2 days and is associated with ischemic brain injury (Broderick et al., 1994). The factors that contribute to the acute fall in cerebral blood flow following subarachnoid hemorrhage (SAH) remain uncertain.Ischemic strokes are caused by blockage of cerebral arteries. In the ischemic neuronal tissue, there is depletion of

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20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat

Cited by 97 publications

References 43 publications

Protective Effect of the 20-HETE Inhibitor HET0016 on Brain Damage after Temporary Focal Ischemia

Protective Effect of the 20-HETE Inhibitor HET0016 on Brain Damage after Temporary Focal Ischemia

Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

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