scholarly journals Pyramidal Cells and Cytochrome P450 Epoxygenase Products in the Neurovascular Coupling Response to Basal Forebrain Cholinergic Input

2012 ◽  
Vol 32 (5) ◽  
pp. 896-906 ◽  
Author(s):  
Clotilde Lecrux ◽  
Ara Kocharyan ◽  
Claire H Sandoe ◽  
Xin-Kang Tong ◽  
Edith Hamel
Keyword(s):  
Cytochrome P450 ◽  
Basal Forebrain ◽  
Primary Source ◽  
Pyramidal Cells ◽  
Doppler Flowmetry ◽  
Vasoactive Mediators ◽  
Excitatory Pathways ◽  
Pharmacological Blockade ◽  
Cox 2 ◽  
Endothelial Nitric Oxide

Activation of the basal forebrain (BF), the primary source of acetylcholine (ACh) in the cortex, broadly increases cortical cerebral blood flow (CBF), a response downstream to ACh release. Although endothelial nitric oxide and cholinoceptive GABA (γ-aminobutyric acid) interneurons have been implicated, little is known about the role of pyramidal cells in this response and their possible interaction with astrocytes. Using c-Fos immunohistochemistry as a marker of neuronal activation and laser-Doppler flowmetry, we measured changes in CBF evoked by BF stimulation following pharmacological blockade of c-Fos-identified excitatory pathways, astroglial metabolism, or vasoactive mediators. Pyramidal cells including those that express cyclooxygenase-2 (COX-2) displayed c-Fos upregulation. Glutamate acting via NMDA, AMPA, and mGlu receptors was involved in the evoked CBF response, NMDA receptors having the highest contribution (∼33%). In contrast, nonselective and selective COX-2 inhibition did not affect the evoked CBF response (+0.4% to 6.9%, ns). The metabolic gliotoxins fluorocitrate and fluoroacetate, the cytochrome P450 epoxygenase inhibitor MS-PPOH and the selective epoxyeicosatrienoic acids (EETs) antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) all blocked the evoked CBF response by ∼50%. Together, the data demonstrate that the hyperemic response to BF stimulation is largely mediated by glutamate released from activated pyramidal cells and by vasoactive EETs, likely originating from activated astrocytes.

scholarly journals Mechanisms of Venoarteriolar Reflex in Type 2 Diabetes with or without Peripheral Neuropathy

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 333
Author(s):  
Cécile Reynès ◽  
Antonia Perez-Martin ◽  
Houda Ennaifer ◽  
Henrique Silva ◽  
Yannick Knapp ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Peripheral Neuropathy ◽  
Spectral Power ◽  
Blood Perfusion ◽  
Doppler Flowmetry ◽  
Relative Contribution ◽  
Total Spectral Power ◽  
Underlying Mechanisms ◽  
Endothelial Nitric Oxide

The aim of this study is to investigate the underlying mechanisms of the venoarteriolar reflex (VAR) in type 2 diabetes mellitus (T2DM), with and without peripheral neuropathy. Laser Doppler flowmetry (LDF) recordings were performed on the medial malleus and dorsal foot skin, before and during leg dependency in healthy controls, in persons with obesity, in those with T2DM, in those with T2DM and subclinical neuropathy, and in those with T2DM and confirmed neuropathy. LDF recordings were analyzed with the wavelet transform to evaluate the mechanisms controlling the flowmotion (i.e., endothelial nitric oxide-independent and -dependent, neurogenic, myogenic, respiratory and cardiac mechanisms). Skin blood perfusion decreased throughout leg dependency at both sites. The decrease was blunted in persons with confirmed neuropathy compared to those with T2DM alone and the controls. During leg dependency, total spectral power increased in all groups compared to rest. The relative contribution of the endothelial bands increased and of the myogenic band decreased, without differences between groups. Neurogenic contribution decreased in controls, in persons with obesity and in those with T2DM, whereas it increased in subclinical- and confirmed neuropathy. In conclusion, this study provides evidence that confirmed diabetic neuropathy alters the VAR through the neurogenic response to leg dependency.

Abstract 111: Xanthine Oxidoreductase Plays a Key Role in Nitrate, Nitrite and Nitric Oxide Homeostasis When the Endothelial Nitric Oxide Synthase is Compromised

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Maria Peleli ◽  
Christa Zollbrecht ◽  
Marcelo Montenegro ◽  
Michael Hezel ◽  
Eddie Weitzberg ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Primary Source ◽  
No Production ◽  
Xanthine Oxidoreductase ◽  
Physiological Conditions ◽  
Inorganic Nitrate ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Xanthine oxidoreductase (XOR) is generally known as a source of superoxide production, but this enzyme has also been suggested to mediate NO production via reduction of inorganic nitrate (NO 3 - ) and nitrite(NO 2 - ). This pathway for NO generation is of particular importance during certain pathologies, whereas endothelial NO synthase (eNOS) is the primary source of vascular NO generation under normal physiological conditions. The exact interplay between the NOS and XOR-derived NO is not yet fully elucidated. The aim of the present study was to investigate if eNOS deficiency is partly compensated by XOR upregulation and sensitization of the NO 3 - - NO 2 - - NO pathway. NO 3 - and NO 2 - were similar between naïve eNOS KO and wildtype (wt) mice, but reduced upon chronic treatment with the non-selective NOS inhibitor L-NAME (wt: 25.0±5.2, eNOS KO: 39.2±6.4, L-NAME: 8.2±1.6 μ NO 3 - -, wt: 0.38±0.07, eNOS KO: 0.42±0.04, L-NAME: 0.12±0.02 μ NO 2 - ). XOR function was upregulated in eNOS KO compared with wt mice [(mRNA: wt 1±0.07, eNOS KO 1.38±0.17), (activity: wt 825±54, eNOS KO 1327±280 CLU/mg/min), (uric acid: wt 32.87±1.53, eNOS KO 43.23±3.54 μ)]. None of these markers of XOR activity was increased in nNOS KO and iNOS KO mice. Following acute dose of NO 3 - (10 mg/kg bw, i.p.), the increase of plasma NO 2 - was more pronounced in eNOS KO (+0.51±0.13 μ) compared with wt (+0.22±0.09 μ), and this augmented response in the eNOS KO was abolished by treatment with the highly selective XOR inhibitor febuxostat (FEB). Liver from eNOS KO had higher reducing capacity of NO 2 - to NO compared with wt, and this effect was attenuated by FEB (Δppb of NO: wt +8.7±4.2, eNOS KO +44.2±15.0, wt+FEB +22.2±9.6, eNOS KO+FEB +26.8±10.2). Treatment with FEB increased blood pressure in eNOS KO (ΔMAP:+10.2±5.6 mmHg), but had no effect in wt (ΔMAP:-0.6±3.3 mmHg). Supplementation with NO 3 - (10 mM, drinking water) reduced blood pressure in eNOS KO (ΔMAP: -6.3±2.2 mmHg), and this effect was abolished by FEB (ΔMAP: +1.1±1.9 mmHg). In conclusion, upregulated and altered XOR function in conditions with eNOS deficiency can facilitate the NO 3 - - NO 2 - - NO pathway and hence play a significant role in vascular NO homeostasis.

Permissive and obligatory roles of NO in cerebrovascular responses to hypercapnia and acetylcholine

1996 ◽  
Vol 271 (4) ◽  
pp. R990-R1001 ◽  
Author(s):  
C. Iadecola ◽  
F. Zhang
Keyword(s):  
Basal Forebrain ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Doppler Flowmetry ◽  
No Donors ◽  
Nos Inhibitors ◽  
Fusion Site ◽  
Nos Inhibitor ◽  
Hypercapnic Response ◽  
Major Mediator

Inhibition of nitric oxide (NO) synthesis attenuates the hypercapnic cerebrovasodilation or the increases in cerebral blood flow (CBF) produced by acetylcholine (ACh), either topically applied or endogenously released in neocortex by stimulation of the basal forebrain cholinergic system. We investigated whether exogenous administration of NO, using NO donors, can reverse the attenuation of these responses by NO synthase (NOS) inhibitors. In halothane-anesthetized, ventilated rats the frontoparietal cortex was exposed and superfused with Ringer. CBF was monitored at the super fusion site by laser-Doppler flowmetry. The basal forebrain was stimulated (100 microA; 50 Hz) with microelectrodes stereotaxically implanted. Superfusion with the NOS inhibitor NG-nitro-L-arginine (L-NNA; 1 mM) reduced resting CBF (-38 +/- 2%; mean +/- SE) and attenuated the vasodilation elicited by hypercapnia (Pco2, 50-60 mmHg; -79 +/- 3%), ACh (10 microM; -83 +/- 7%), or basal forebrain stimulation (-44 +/- 2%) (P < 0.05, analysis of variance and Tukey's test). After L-NNA, topical application of 3-morpholinosydnonimine (SIN-1) (n = 7), S-nitroso-N-acetylpenicillamine (SNAP) (n = 6), or 8-bromoguanosine 3',5'-monophosphate (8-BrcGMP, n = 4) reestablished resting CBF (P > 0.05 from Ringer) and reversed the attenuation of the response to hypercapnia (P > 0.05 from Ringer). However, SIN-1 or SNAP failed to reverse the attenuation of the response to basal forebrain stimulation or topical ACh (P > 0.05 from L-NNA). After L-NNA, the NO-independent vasodilator papaverine (n = 4) reestablished resting CBF (P > 0.05 from Ringer) but failed to restore the hypercapnic vasodilation (P > 0.05 from L-NNA). The attenuation of hypercapnic response by the neuronal NOS inhibitor 7-nitroindazole was counteracted only partially by SIN-1 (n = 4) or 8-BrcGMP (n = 4). The data support the hypothesis that the vasodilation elicited by hypercapnia requires resting levels of NO for its expression, whereas the response to endogenous or exogenous ACh depends on agonist-induced NOS activation. In hypercapnia NO may act as a permissive factor by facilitating the action of other vasodilators, whereas in the vascular response initiated by ACh NO is likely to be the major mediator of smooth muscle relaxation.

Neurotransmitters in the cerebral cortex

1986 ◽  
Vol 65 (2) ◽  
pp. 135-153 ◽  
Author(s):  
Edward G. Jones
Keyword(s):  
Cerebral Cortex ◽  
Basal Forebrain ◽  
Cortical Neurons ◽  
Pyramidal Cells ◽  
Gamma Aminobutyric Acid ◽  
Content Type ◽  
Disease States ◽  
Afferent Fibers ◽  
Cortical Interneurons ◽  
Fine Print

✓ This article surveys the conventional neurotransmitters and modulatory neuropeptides that are found in the cerebral cortex and attempts to place them into the perspective of both intracortical circuitry and cortical disease. The distribution of these substances is related, where possible, to particular types of cortical neuron or to afferent or efferent fibers. Their physiological actions, where known, on cortical neurons are surveyed, and their potential roles in disease states such as the dementias, epilepsy, and stroke are assessed. Conventional transmitters that occur in afferent fibers to the cortex from brain-stem and basal forebrain sites are: serotonin, noradrenaline, dopamine, and acetylcholine. All of these except dopamine are distributed to all cortical areas: dopamine is distributed to frontal and cingulate areas only. The transmitter in thalamic afferent systems is unknown. Gamma aminobutyric acid (GABA) is the transmitter used by the majority of cortical interneurons and has a profound effect upon the shaping of receptive field properties. The vast majority of the known cortical peptides are found in GABAergic neurons, and the possibility exists that they may act as trophic substances for other neurons. Levels of certain neuropeptides decline in cases of dementia of cortical origin. Acetylcholine is the only other known transmitter of cortical neurons. It, too, is contained in neurons that also contain a neuropeptide. The transmitter(s) used by excitatory cortical interneurons and by the efferent pyramidal cells is unknown, but it may be glutamate or aspartate. It is possible that excitotoxins released in anoxic disease of the cortex may produce damage by acting on receptors for these or related transmitter agents.

scholarly journals Vascular protection and regenerative effects of intranasal DL-3-N-butylphthalide treatment after ischaemic stroke in mice

2020 ◽  
pp. svn-2020-000364
Author(s):  
Mengyao Qu ◽  
Jingjie Zhao ◽  
Yingying Zhao ◽  
Jinmei Sun ◽  
Liping Liu ◽  
...  
Keyword(s):  
Ischaemic Stroke ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Vehicle Group ◽  
Sensorimotor Function ◽  
Vascular Protection ◽  
Doppler Flowmetry ◽  
Infarct Region ◽  
Common Carotid Artery Occlusion ◽  
Endothelial Nitric Oxide

ObjectiveTo investigate the effects of DL-3-N-butylphthalide (NBP) via intranasal delivery after ischaemic stroke in mice.MethodsC57BL/6 mice were divided into three groups: sham, stroke with vehicle and stroke with NBP treatment. Ischaemic stroke was induced by permanent ligation of right middle cerebral artery with 7 min common carotid artery occlusion. NBP (100 mg/kg) or vehicle was intranasally administered at 1 hour after stroke and repeated once a day until sacrifice. Bromodeoxyuridine (BrdU) (50 mg/kg/day) was given from the third day until sacrifice. Sensorimotor function was tested during 1–21 days after stroke. Local cerebral blood flow in the ischaemic and peri-infarct regions was measured using laser Doppler flowmetry before, during and 3 days after ischaemia. Expressions of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase as well as regenerative marker BrdU in the peri-infarct region were analysed by western blotting and immunohistochemical methods.ResultsCompared with the vehicle group, NBP treatment significantly increased the VEGF expression in the poststroke brain. Stroke mice that received NBP showed significantly less vascular damage after stroke and more new neurons and blood vessels in the peri-infarct region at 21 days after stroke. In the adhesive removal test, the sensorimotor function of stroke mice treated with NBP performed significantly better at 1, 3 and 7 days after stroke compared with vehicle controls.ConclusionDaily intranasal NBP treatment provides protective and neurogenic/angiogenic effects in the poststroke brain, accompanied with functional improvements after a focal ischaemic stroke in mice.

scholarly journals Peroxisome Proliferator-Activated Receptor-αActivation Decreases Mean Arterial Pressure, Plasma Interleukin-6, and COX-2 While Increasing Renal CYP4A Expression in an Acute Model of DOCA-Salt Hypertension

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Dexter L. Lee ◽  
Justin L. Wilson ◽  
Rong Duan ◽  
Tamaro Hudson ◽  
Ahmed El-Marakby
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Interleukin 6 ◽  
Corn Oil ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Salt Hypertension ◽  
Cox 2

Peroxisome proliferator-activated receptor-alpha (PPAR-α) activation by fenofibrate reduces blood pressure and sodium retention during DOCA-salt hypertension. PPAR-αactivation reduces the expression of inflammatory cytokines, such as interleukin-6 (IL-6). Fenofibrate also induces cytochrome P450 4A (CYP4A) and increases 20-hydroxyeicosatetraenoic acid (20-HETE) production. This study tested whether the administration of fenofibrate would reduce blood pressure by attenuating plasma IL-6 and renal expression of cyclooxygenase-2 (COX-2), while increasing expression of renal CYP4A during 7 days of DOCA-salt hypertension. We performed uni-nephrectomy on 12–14 week old male Swiss Webster mice and implanted biotelemetry devices in control, DOCA-salt (1.5 mg/g) treated mice with or without fenofibrate (500 mg/kg/day in corn oil, intragastrically). Fenofibrate significantly decreased mean arterial pressure and plasma IL-6. In kidney homogenates, fenofibrate increased CYP4A and decreased COX-2 expression. There were no differences in renal cytochrome P450, family 2, subfamily c, polypeptide 23 (CYP2C23) and soluble expoxide hydrolase (sEH) expression between the groups. Our results suggest that the blood pressure lowering effect of PPAR-αactivation by fenofibrate involves the reduction of plasma IL-6 and COX-2, while increasing CYP4A expression during DOCA-salt hypertension. Our results may also suggest that PPAR-αactivation protects the kidney against renal injury via decreased COX-2 expression.

Early vasodilator response to anodal current application in human is not impaired by cyclooxygenase-2 blockade

2005 ◽  
Vol 288 (4) ◽  
pp. H1668-H1673 ◽  
Author(s):  
Maylis Tartas ◽  
Philippe Bouyé ◽  
Audrey Koïtka ◽  
Sylvain Durand ◽  
Yves Gallois ◽  
...  
Keyword(s):  
Neurogenic Inflammation ◽  
Current Application ◽  
Primary Afferent ◽  
Axon Reflex ◽  
Doppler Flowmetry ◽  
Cutaneous Vasodilatation ◽  
Afferent Fibers ◽  
Primary Afferent Fibers ◽  
Cox 2 ◽  
Cox 1

It is generally acknowledged that cutaneous vasodilatation in response to monopolar galvanic current application would result from an axon reflex in primary afferent fibers and the neurogenic inflammation resulting from neuropeptide release. Previous studies suggested participation of prostaglandin (PG) in anodal current-induced cutaneous vasodilatation. Thus the inducible cyclooxygenase (COX) isoform (COX-2), assumed to play a key role in inflammation, should be involved in the synthesis of the PG that is released. Skin blood flow (SkBF) variations induced by 5 min of 0.1-mA monopolar anodal current application were evaluated with laser-Doppler flowmetry on the forearm of healthy volunteers treated with indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), or placebo. SkBF was indexed as cutaneous vascular conductance (CVC), expressed as percentage of heat-induced maximal CVC (%MVC). Urinalyses were performed to test celecoxib treatment efficiency. No difference was found in CVC values at rest: 14.3 ± 4.0, 11.9 ± 3.2, and 10.9 ± 2.0% MVC after indomethacin, celecoxib, and placebo treatment, respectively. At 10 min after the onset of anodal current application, CVC values were 22.2 ± 4.9% MVC (not significantly different from rest) with indomethacin, 85.7 ± 15.3% MVC ( P < 0.001 vs. rest) with celecoxib, and 70.4 ± 13.1% MVC ( P < 0.001 vs. rest) with placebo. Celecoxib significantly depressed the urinary prostacyclin metabolite 6-keto-PGF1α ( P < 0.05 vs. placebo). Indomethacin, but not celecoxib, significantly inhibited the anodal current-induced vasodilatation. Thus, although they are assumed to result from an axon reflex in primary afferent fibers and neurogenic inflammation, these results suggest that the early anodal current-induced vasodilatation is mainly dependent on COX-1-induced PG synthesis.

Prostaglandin modulation of the gastric vasculature and mucosal integrity in cirrhotic rats

1993 ◽  
Vol 265 (3) ◽  
pp. G453-G458 ◽  
Author(s):  
P. L. Beck ◽  
W. McKnight ◽  
S. S. Lee ◽  
J. L. Wallace
Keyword(s):  
Ex Vivo ◽  
Prostaglandin Synthesis ◽  
Gastric Injury ◽  
Gastric Bleeding ◽  
Doppler Flowmetry ◽  
Mucosal Integrity ◽  
Endogenous Prostaglandin ◽  
Vasoactive Mediators ◽  
Duct Ligation ◽  
Endogenous Prostaglandins

Gastric bleeding is a frequent occurrence in cirrhotic patients and may be related to altered microcirculatory responses to luminal irritants and/or vasoactive mediators. Because gastric prostaglandin synthesis has been reported to be altered in cirrhosis, we have examined the role of prostaglandins in modulating gastric perfusion velocity and mucosal integrity in cirrhotic rats. Cirrhosis was induced by bile duct ligation. Gastric perfusion velocity was measured in an ex vivo gastric chamber preparation by laser-Doppler flowmetry. The responsiveness of the mucosa to topical application of 20% ethanol was assessed. Effects of pretreatment with indomethacin or misoprostol were also determined. Gastric and hepatic prostaglandin E2 syntheses were significantly depressed (by approximately 60%) in cirrhotic vs. normal rats. Administration of indomethacin (7.5 mg/kg) to normal rats did not significantly affect gastric perfusion velocity, but in cirrhotic rats it caused a 45% reduction (P < 0.05). Topically applied misoprostol produced significantly greater (2- to 5-fold) increases in gastric perfusion velocity in cirrhotics than in controls. Cirrhotic rats were significantly more susceptible to gastric injury induced by topically applied 20% ethanol than were controls. These results suggest that gastric perfusion velocity in cirrhotic rats is modulated by endogenous prostaglandins to a much greater degree than in controls. Gastric vascular hyperresponsiveness to misoprostol may be attributable to an adaptive response to depressed endogenous prostaglandin synthesis in the cirrhotic animals.

Chronic elevation of IL-1β induces diuresis via a cyclooxygenase 2-mediated mechanism

2013 ◽  
Vol 305 (2) ◽  
pp. F189-F198 ◽  
Author(s):  
E. I. Boesen
Keyword(s):  
Critical Role ◽  
Urine Flow ◽  
Vehicle Group ◽  
Prostaglandin E ◽  
Disease States ◽  
Pharmacological Blockade ◽  
Cox 2 ◽  
Oxide Synthase ◽  
Nos Isoforms ◽  
The Impact

Chronic renal inflammation is an increasingly recognized phenomenon in multiple disease states, but the impact of specific cytokines on renal function is unclear. Previously, we found that 14-day interleukin-1β (IL-1β) infusion increased urine flow in mice. To determine the mechanism by which this occurs, the current study tested the possible involvement of three classical prodiuretic pathways. Chronic IL-1β infusion significantly increased urine flow (6.5 ± 1 ml/day at day 14 vs. 2.3 ± 0.3 ml/day in vehicle group; P < 0.05) and expression of cyclooxygenase (COX)-2, all three nitric oxide synthase (NOS) isoforms, and endothelin (ET)-1 in the kidney ( P < 0.05 in all cases). Urinary prostaglandin E metabolite (PGEM) excretion was also significantly increased at day 14 of IL-1β infusion (1.21 ± 0.26 vs. 0.29 ± 0.06 ng/day in vehicle-infused mice; P = 0.001). The selective COX-2 inhibitor celecoxib markedly attenuated urinary PGEM excretion and abolished the diuretic response to chronic IL-1β infusion. In contrast, deletion of NOS3, or inhibition of NOS1 with l-VNIO, did not blunt the diuretic effect of IL-1β, nor did pharmacological blockade of endothelin ETAand ETBreceptors with A-182086. Consistent with a primary effect on water transport, IL-1β infusion markedly reduced inner medullary aquaporin-2 expression ( P < 0.05) and did not alter urinary Na+or K+excretion. These data indicate a critical role for COX-2 in mediating the effects of chronic IL-1β elevation on the kidney.

scholarly journals Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression—Evoked cerebral oligemia

2016 ◽  
Vol 37 (3) ◽  
pp. 1060-1068 ◽  
Author(s):  
Helaine Gariepy ◽  
Jun Zhao ◽  
Dan Levy
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Selective Inhibition ◽  
Doppler Flowmetry ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Synthase Inhibitor ◽  
Later Phase ◽  
Cox 1

Cortical spreading depression (CSD) is considered a significant phenomenon for human neurological conditions and one of its key signatures is the development of persistent cortical oligemia. The factors underlying this reduction in cerebral blood flow (CBF) remain incompletely understood but may involve locally elaborated vasoconstricting eicosanoids. We employed laser Doppler flowmetry in urethane-anesthetized rats, together with a local pharmacological blockade approach, to test the relative contribution of cyclooxygenase (COX)-derived prostanoids to the oligemic response following CSD. Administration of the non-selective COX inhibitor naproxen completely inhibited the oligemic response. Selective inhibition of COX-1 with SC-560 preferentially reduced the early reduction in CBF while selective COX-2 inhibition with NS-398 affected only the later response. Blocking the action of thromboxane A2 (TXA2), using the selective thromboxane synthase inhibitor ozagrel, reduced only the initial CBF decrease, while inhibition of prostaglandin F2alpha action, using the selective FP receptor antagonist AL-8810, blocked the later phase of the oligemia. Our results suggest that the long-lasting oligemia following CSD consists of at least two distinct temporal phases, mediated by preferential actions of COX-1- and COX-2-derived prostanoids: an initial phase mediated by COX-1 that involves TXA2 followed by a later phase, mediated by COX-2 and PGF2alpha.

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