Production of 20-HETE and Its Role in Autoregulation of Cerebral Blood Flow

Gebremedhin, Debebe; Lange, Andrew R.; Lowry, T. F.; Taheri, M. Reza; Birks, Eric K.; Hudetz, Antal G.; Narayanan, Jayashree; Falck, John R.; Okamoto, Hirotsugu; Roman, Richard J.; Nithipatikom, Kasem; Campbell, William B.; Harder, David R.

doi:10.1161/01.res.87.1.60

Cited by 285 publications

(290 citation statements)

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“…This finding is consistent with previous work demonstrating that PG is released from glial cells (22,23), and that 20-HETE synthesis occurs downstream at the level of vascular smooth muscle cells (24). These results also clarify why we did not previously observe a PG component of neurovascular coupling in the ex vivo retina (6); that earlier ex vivo study was conducted entirely in 95% O 2 , effectively suppressing the PG component of the response.…”

Section: Discussionsupporting

confidence: 92%

Oxygen modulation of neurovascular coupling in the retina

Mishra

Hamid

Newman

2011

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

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Neurovascular coupling is a process through which neuronal activity leads to local increases in blood flow in the central nervous system. In brain slices, 100% O 2 has been shown to alter neurovascular coupling, suppressing activity-dependent vasodilation. However, in vivo, hyperoxia reportedly has no effect on blood flow. Resolving these conflicting findings is important, given that hyperoxia is often used in the clinic in the treatment of both adults and neonates, and a reduction in neurovascular coupling could deprive active neurons of adequate nutrients. Here we address this issue by examining neurovascular coupling in both ex vivo and in vivo rat retina preparations. In the ex vivo retina, 100% O 2 reduced light-evoked arteriole vasodilations by 3.9-fold and increased vasoconstrictions by 2.6-fold. In vivo, however, hyperoxia had no effect on light-evoked arteriole dilations or blood velocity. Oxygen electrode measurements showed that 100% O 2 raised pO 2 in the ex vivo retina from 34 to 548 mm Hg, whereas hyperoxia has been reported to increase retinal pO 2 in vivo to only ∼53 mm Hg [Yu DY, Cringle SJ, Alder VA, Su EN (1994) Am J Physiol 267:H2498-H2507]. Replicating the hyperoxic in vivo pO 2 of 53 mm Hg in the ex vivo retina did not alter vasomotor responses, indicating that although O 2 can modulate neurovascular coupling when raised sufficiently high, the hyperoxia-induced rise in retinal pO 2 in vivo is not sufficient to produce a modulatory effect. Our findings demonstrate that hyperoxia does not alter neurovascular coupling in vivo, ensuring that active neurons receive an adequate supply of nutrients.functional hyperemia | glial cells | prostaglandins N euronal activity in the CNS induces local increases in blood flow (1, 2), a homeostatic response termed functional hyperemia. Neurovascular coupling, the process mediating this response, is thought to involve signaling from neurons to glial cells to blood vessels. Neuronal activity induces a rise in intracellular Ca 2+ in glial cell endfeet surrounding vessels, leading to the release of vasoactive arachidonic acid metabolites and resulting in vasomotor responses (2-6). Experiments in brain slices and in the ex vivo retina have revealed that glial activation can evoke both vasodilation and vasoconstriction. Evoked vasodilations are mediated by cyclooxygenase (COX) products (3, 5) and epoxyeicosatrienoic acids (EETs) (6-9), whereas vasoconstrictions are mediated by 20-hydroxyeicosatetraenoic acid (20-HETE) (4,6).A recent study demonstrated that neurovascular coupling is modulated by O 2 in brain slices (10). Both neuronal and glial cell stimulation elicited vasodilations in brain slices exposed to 20% O 2 . In contrast, vasoconstrictions were evoked in the presence of 100% O 2 . However, another recent study reported the opposite effect of O 2 in vivo (11). In that study, increasing systemic O 2 using hyperbaric hyperoxygenation had no effect on cortical functional hyperemia. Resolving these conflicting findings is critical, given that hyperoxia (breat...

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Section: Discussionsupporting

confidence: 92%

Oxygen modulation of neurovascular coupling in the retina

Mishra

Hamid

Newman

2011

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

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“…20-Hydroxyeicosatetraenoic acid (20-HETE) is one of the AA metabolites produced by some CYP isozymes, which we termed 20-HETE synthase, mainly by CYP4A and 4F (Laethem et al, 1992;Roman, 2002). It has been reported that 20-HETE acts as a potent vasoconstrictor of cerebral microvessels (Harder et al, 1994), and has an important role in the autoregulation of cerebral blood flow (Gebremedhin et al, 2000). 20-Hydroxyeicosatetraenoic acid has also been reported to induce the formation of oxygen radicals by interacting with nicotinamide adenine dinucleotide phosphate-oxidase and nitric oxide synthase (Wang et al, 2006;Cheng et al, 2008;Medhora et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Increase of 20-HETE Synthase after Brain Ischemia in Rats Revealed by PET Study with ¹¹C-Labeled 20-HETE Synthase-Specific Inhibitor

Kawasaki

Marumo

Shirakami

et al. 2012

J Cereb Blood Flow Metab

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20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a 11 C-labeled specific 20-HETE synthase inhibitor, N 0 (4-dimethylaminohexyloxy)phenyl imidazole ([ 11 C]TROA). Autoradiographic study showed that [ 11 C]TROA has highspecific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [ 11 C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [ 11 C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [ 11 C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia.

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“…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).…”

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confidence: 99%

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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Production of 20-HETE and Its Role in Autoregulation of Cerebral Blood Flow

Cited by 285 publications

References 22 publications

Oxygen modulation of neurovascular coupling in the retina

Oxygen modulation of neurovascular coupling in the retina

Increase of 20-HETE Synthase after Brain Ischemia in Rats Revealed by PET Study with ¹¹C-Labeled 20-HETE Synthase-Specific Inhibitor

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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Production of 20-HETE and Its Role in Autoregulation of Cerebral Blood Flow

Cited by 285 publications

References 22 publications

Oxygen modulation of neurovascular coupling in the retina

Oxygen modulation of neurovascular coupling in the retina

Increase of 20-HETE Synthase after Brain Ischemia in Rats Revealed by PET Study with 11C-Labeled 20-HETE Synthase-Specific Inhibitor

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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Increase of 20-HETE Synthase after Brain Ischemia in Rats Revealed by PET Study with ¹¹C-Labeled 20-HETE Synthase-Specific Inhibitor