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.

Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus

1999 ◽  
Vol 276 (3) ◽  
pp. R913-R921 ◽  
Author(s):  
Ronald I. Clyman ◽  
Pierre Hardy ◽  
Nahid Waleh ◽  
Yao Qi Chen ◽  
Françoise Mauray ◽  
...  
Keyword(s):  
Significant Role ◽  
Ductus Arteriosus ◽  
Late Gestation ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Fetal Lamb ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.

Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys

2006 ◽  
Vol 290 (4) ◽  
pp. F897-F904 ◽  
Author(s):  
Lori Warford-Woolgar ◽  
Claudia Yu-Chen Peng ◽  
Jamie Shuhyta ◽  
Andrew Wakefield ◽  
Deepa Sankaran ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Relative Difference ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Relative Contribution ◽  
Prostanoid Production ◽  
Prostaglandin F ◽  
Cox 2 ◽  
Cox 1

Renal prostanoids are important regulators of normal renal function and maintenance of renal homeostasis. In diseased kidneys, renal cylooxygenase (COX) expression and prostanoid formation are altered. With the use of the Han:Sprague-Dawley- cy rat, the aim of this study was to determine the relative contribution of renal COX isoforms (protein, gene expression, and activity) on renal prostanoid production [thromboxane B2 (TXB2, stable metabolite of TXA2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1α (6-keto-PGF1α, stable metabolite of PGI2)] in normal and diseased kidneys. In diseased kidneys, COX-1-immunoreactive protein and mRNA levels were higher and COX-2 levels were lower compared with normal kidneys. In contrast, COX activities were higher in diseased compared with normal kidneys for both COX-1 [0.05 ± 0.02 vs. 0.45 ± 0.11 ng prostanoids·min−1·mg protein−1 ( P < 0.001)] and COX-2 [0.64 ± 0.10 vs. 2.32 ± 0.22 ng prostanoids·min−1·mg protein−1 ( P < 0.001)]. As the relative difference in activity was greater for COX-1, the ratio of COX-1/COX-2 was higher in diseased compared with normal kidneys, although the predominant activity was still due to the COX-2 isoform in both genotypes. Endogenous and steady-state in vitro levels of prostanoids were ∼2–10 times higher in diseased compared with normal kidneys. The differences between normal and diseased kidney prostanoids were in the order of TXB2 > 6-keto-PGF1α > PGE2, as determined by higher renal prostanoid levels and COX activity ratios of TXB2/6-keto-PGF1α, TXB2/PGE2, and 6-keto-PGF1α/PGE2. This specificity in both the COX isoform type and for the prostanoids produced has implications for normal and diseased kidneys in treatments involving selective inhibition of COX isoforms.

Mechanisms underlying the contraction induced by bradykinin in the guinea pig epithelium-denuded trachea

2002 ◽  
Vol 80 (4) ◽  
pp. 360-367 ◽  
Author(s):  
Valfredo Schlemper ◽  
João B Calixto
Keyword(s):  
Nitric Oxide ◽  
Guinea Pig ◽  
Rank Order ◽  
Nitric Oxide Synthase Inhibitor ◽  
Cox Inhibitors ◽  
Cyclooxygenase 1 ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Synthase Inhibitor ◽  
Cox 1

This study investigates some of the mechanisms by which bradykinin (BK) triggers contraction of epithelium-denuded strips of guinea pig trachea (GPT). Cumulative or single additions of BK, T-BK, L-BK, or ML-BK in the presence of captopril (30 µM) produced graded GPT contractions with the following rank order of potency (EC50 level): T-BK (31.3 nM) > BK (40.0 nM) > L-BK (56.0 nM) > ML-BK (77.0 nM). BK-induced contraction (100 nM) in GPT was completely inhibited by either HOE 140 or NPC 17731 with mean IC50 values of 17 and 217 nM, respectively. Addition of BK (100 nM) at 30 min intervals, induced progressive tachyphylaxis, which was complete after 4 h. The tachyphylaxis induced by BK was unaffected by L-NOARG (nitric oxide synthase inhibitor, 100 µM) or valeryl salicylate (a cyclooxygenase-1 (COX-1) inhibitor, 30 µM), but was prevented by a low concentration of indomethacin, diclofenac (non-selective COX inhibitors, 3 nM each) or by NS 398 (a COX-2 inhibitor, 10 nM). Furthermore, higher concentrations of indomethacin, diclofenac, phenidone (a lypooxygenase (LOX) and COX inhibitor), or NS 398, caused graded inhibition of BK-induced contraction, with mean IC50 values of 0.28, 0.08, 46.37, and 0.15 µM, respectively. Together, these results suggest that BK-induced contraction in GPT involves activation of B2 receptors and release of prostanoids from COX-2 pathway. Furthermore, the tachyphylaxis induced by BK was insensitive to the nitric oxide and COX-1 inhibitors, but was prevented by non-selective and selective COX-2 inhibitors, indicating a mediation via COX-2-derived arachidonic acid metabolites.Key words: guinea pig trachea, bradykinin, B2 receptors, desensitization, prostaglandins.

scholarly journals Intrarenal expression and distribution of cyclooxygenase isoforms in rats with experimental heart failure

2001 ◽  
Vol 280 (1) ◽  
pp. F43-F53 ◽  
Author(s):  
Zaid Abassi ◽  
Sergey Brodsky ◽  
Olga Gealekman ◽  
Irith Rubinstein ◽  
Aaron Hoffman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Flow ◽  
Western Blot ◽  
Renal Medulla ◽  
Renal Perfusion ◽  
Rt Pcr ◽  
Doppler Flowmetry ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Cox 1

The generation of PGs from arachidonic acid is mediated by cyclooxygenase (COX), which consists of a constitutive (COX-1) and an inducible (COX-2) isoform. The present study evaluated the relative expression and immunoreactive levels of COX-1 and COX-2, by means of RT-PCR, Western blot analysis, and immunohistochemistry, in the renal cortex and medulla of rats with congestive heart failure (CHF), induced by the placement of an aortocaval fistula. In addition, we examined the effects of a COX-1 inhibitor (piroxicam), COX-2 inhibitor (nimesulide), and nonselective COX inhibitor (indomethacin) at a dose of 5 mg/kg, on intrarenal blood flow by laser Doppler flowmetry. COX-1 and COX-2 mRNAs were abundantly expressed in the renal medulla of control and CHF rats and only minimally in the cortex. Moreover, both RT-PCR (32–36 cycles) and Western blot techniques revealed upregulation of medullary COX-2, but not of COX-1, in rats with advanced heart failure. In line with these findings, all three tested COX inhibitors provoked significant and sustained decreases (Δ ≈ −20%) in medullary blood flow (MBF), which were similar in magnitude and duration in control animals. However, in CHF rats, indomethacin produced a greater reduction in MBF than that obtained with either piroxicam or nimesulide. Taken together, these results indicate that 1) both COX-1 and COX-2 are predominantly expressed in the renal medulla and 2) experimental CHF is associated with selective overexpression of COX-2. The latter may represent a mechanism aimed at defending MBF in the face of a decrease in renal perfusion pressure during the development of CHF.

scholarly journals Cyclooxygenase-dependent mechanisms mediate in part the anti-dilatory effects of perivascular adipose tissue in uterine arteries from pregnant rats

2021 ◽  
Author(s):  
Oluwatobiloba Osikoya ◽  
Spencer C. Cushen ◽  
Styliani Goulopoulou
Keyword(s):  
Adipose Tissue ◽  
Selective Inhibition ◽  
Response Curves ◽  
Pregnant Rats ◽  
Perivascular Adipose Tissue ◽  
Uterine Arteries ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Relaxation Responses ◽  
Cox 1

AbstractUterine perivascular adipose tissue (PVAT) contributes to uterine blood flow regulation in pregnancy, at least in part, due to its effects on uterine artery reactivity. Here, we investigated the effects of uterine PVAT on endothelium-dependent pathways involved in relaxation of main uterine arteries. We hypothesized that uterine PVAT modulates the balance between the contribution of nitric oxide synthase (NOS)- and cyclooxygenase (COX)-dependent pathways to acetylcholine (ACh)-induced relaxation in isolated uterine arteries. Concentration-response curves to ACh (1 nM – 30 µM) were performed on main uterine arteries from pregnant and non-pregnant rats. Arteries were exposed to Krebs-Henseleit solution (control) or PVAT-conditioned media (PVATmedia) in the presence of the following inhibitors: L-NAME (100 µM), indomethacin (COX inhibitor, 10 µM), SC560 (selective COX-1 inhibitor, 1 µM), NS398 (selective COX-2 inhibitor, 1 µM), SQ 29,548 (selective thromboxane receptor (TP) inhibitor, 1 µM). Indomethacin suppressed ACh-induced relaxation in control uterine arteries from pregnant rats (p<0.0001) but not in non-pregnant rats (p>1.0). In arteries incubated with PVATmedia, the presence of indomethacin increased ACh-induced relaxation, reversing the anti-dilatory effect of PVATmedia. NOS inhibition reduced ACh-induced relaxation in uterine arteries from pregnant rats, and exposure to PVATmedia did not change this effect. Selective inhibition of COX-1 but not COX-2 suppressed relaxation responses to ACh in control arteries. The presence of PVATmedia abolished the effect COX-1 inhibition. Incubation of uterine arteries from pregnant rats with PVATmedia increased production of thromboxane B2 (TxB2, p=0.01). TP inhibition did not have any effect on the anti-dilatory properties of PVATmedia. In conclusion, uterine PVAT releases transferable factors that reduce relaxation responses to ACh via a COX-dependent mechanism in isolated uterine arteries from pregnant rats.

scholarly journals Hypoxia and Hypotension Transform the Blood Flow Response to Cortical Spreading Depression from Hyperemia into Hypoperfusion in the Rat

2008 ◽  
Vol 28 (7) ◽  
pp. 1369-1376 ◽  
Author(s):  
Inna Sukhotinsky ◽  
Ergin Dilekoz ◽  
Michael A Moskowitz ◽  
Cenk Ayata
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Ischemic Penumbra ◽  
Doppler Flowmetry ◽  
Blood Flow Response ◽  
Flow Response ◽  
Normal Rat ◽  
Cortex Cérébral

Cortical spreading depression (CSD) evokes a large cerebral blood flow (CBF) increase in normal rat brain. In contrast, in focal ischemic penumbra, CSD-like periinfarct depolarizations (PID) are mainly associated with hypoperfusion. Because PIDs electrophysiologically closely resemble CSD, we tested whether conditions present in ischemic penumbra, such as tissue hypoxia or reduced perfusion pressure, transform the CSD-induced CBF response in nonischemic rat cortex. Cerebral blood flow changes were recorded using laser Doppler flowmetry in rats subjected to hypoxia, hypotension, or both. Under normoxic normotensive conditions, CSD caused a characteristic transient CBF increase (74 ± 7%) occasionally preceded by a small hypoperfusion (−4 ± 2%). Both hypoxia ( pO2 45 ± 3 mm Hg) and hypotension (blood pressure 42 ± 2 mm Hg) independently augmented this initial hypoperfusion (−14 ± 2% normoxic hypotension; −16 ± 6% hypoxic normotension; −21 ± 5% hypoxic hypotension) and diminished the magnitude of hyperemia (44 ± 10% normoxic hypotension; 43 ± 9% hypoxic normotension; 27 ± 6% hypoxic hypotension). Hypotension and, to a much lesser extent, hypoxia increased the duration of hypoperfusion and the DC shift, whereas CSD amplitude remained unchanged. These results suggest that hypoxia and/or hypotension unmask a vasoconstrictive response during CSD in the rat such that, under nonphysiologic conditions (i.e., mimicking ischemic penumbra), the hyperemic response to CSD becomes attenuated resembling the blood flow response during PIDs.

Sa1096 SELECTIVE INHIBITION OF COX-1, BUT NOT COX-2, DECREASED THE COLONIC EPITHELIAL INTEGRITY IN THE TNBS-INDUCED COLITIS IN RATS.

2020 ◽  
Vol 158 (6) ◽  
pp. S-274
Author(s):  
Humberto B. da Costa ◽  
Thiago M. Sales ◽  
Suliana M. Paula ◽  
Rodrigo C. Mourão ◽  
Maria Klayre A. Sousa ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Epithelial Integrity ◽  
Cox 2 ◽  
Cox 1

scholarly journals Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans

2007 ◽  
Vol 293 (1) ◽  
pp. H425-H432 ◽  
Author(s):  
Marvin S. Medow ◽  
Indu Taneja ◽  
Julian M. Stewart
Keyword(s):  
Nitric Oxide ◽  
Peak Flow ◽  
Reactive Hyperemia ◽  
Laser Doppler ◽  
Doppler Flowmetry ◽  
Time To Peak ◽  
Flow Parameters ◽  
Cox Inhibitor ◽  
Cutaneous Circulation ◽  
Synthase Inhibitor

We tested the hypothesis that cyclooxygenases (COXs) or COX products inhibit nitric oxide (NO) synthesis and thereby mask potential effects of NO on reactive hyperemia in the cutaneous circulation. We performed laser-Doppler flowmetry (LDF) with intradermal microdialysis in 12 healthy volunteers aged 19–25 yr. LDF was expressed as the percent cutaneous vascular conduction (%CVC) or as the maximum %CVC (%CVCmax) where CVC is LDF/mean arterial pressure. We tested the effects of the nonisoform-specific NO synthase inhibitor nitro-l-arginine (NLA, 10 mM), the nonspecific COX inhibitor ketorolac (Keto, 10 mM), combined NLA + Keto, and NLA + sodium nitroprusside (SNP, 28 mM) on baseline and reactive hyperemia flow parameters. We also examined the effects of isoproterenol, a β-adrenergic agonist that causes prostaglandin-independent vasodilation to correct for the increase in baseline flow caused by Keto. When delivered directly into the intradermal space, Keto greatly augments all aspects of the laser-Doppler flow response to reactive hyperemia: peak reactive hyperemic flow increased from 41 ± 5 to 77 ± 7%CVCmax, time to peak flow increased from 17 ± 3 to 56 ± 24 s, the area under the reactive hyperemic curve increased from 1,417 ± 326 to 3,376 ± 876%CVCmax·s, and the time constant for the decay of peak flow increased from 100 ± 23 to 821 ± 311 s. NLA greatly attenuates the Keto response despite exerting no effects on baseline LDF or on reactive hyperemia when given alone. Low-dose NLA + SNP duplicates the Keto response. Isoproterenol increased baseline and peak reactive flow. These results suggest that COX inhibition unmasks NO dependence of reactive hyperemia in human cutaneous circulation.

scholarly journals Cyclosporine A, FK506, and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression

2011 ◽  
Vol 31 (7) ◽  
pp. 1588-1598 ◽  
Author(s):  
Henning Piilgaard ◽  
Brent M Witgen ◽  
Peter Rasmussen ◽  
Martin Lauritzen
Keyword(s):  
Cyclosporine A ◽  
Cortical Spreading Depression ◽  
Vascular Reactivity ◽  
Spreading Depression ◽  
Mitochondrial Permeability Transition ◽  
Neurovascular Coupling ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Doppler Flowmetry ◽  
Electrocortical Activity

Cortical spreading depression (CSD) is associated with mitochondrial depolarization, increasing intracellular Ca2+, and the release of free fatty acids, which favor opening of the mitochondrial permeability transition pore (mPTP) and activation of calcineurin (CaN). Here, we test the hypothesis that cyclosporine A (CsA), which blocks both mPTP and CaN, ameliorates the persistent reduction of cerebral blood flow (CBF), impaired vascular reactivity, and a persistent rise in the cerebral metabolic rate of oxygen (CMRO2) following CSD. In addition to CsA, we used the specific mPTP blocker NIM811 and the specific CaN blocker FK506. Cortical spreading depression was induced in rat frontal cortex. Electrocortical activity was recorded by glass microelectrodes, CBF by laser Doppler flowmetry, and tissue oxygen tension with polarographic microelectrodes. Electrocortical activity, basal CBF, CMRO2, and neurovascular and neurometabolic coupling were unaffected by all three drugs under control conditions. NIM811 augmented the rise in CBF observed during CSD. Cyclosporine A and FK506 ameliorated the persistent decrease in CBF after CSD. All three drugs prevented disruption of neurovascular coupling after CSD; the rise in CMRO2 was unchanged. Our data suggest that blockade of mPTP formation and CaN activation may prevent persistent CBF reduction and vascular dysfunction after CSD.

scholarly journals Persistent Increase in Oxygen Consumption and Impaired Neurovascular Coupling after Spreading Depression in Rat Neocortex

2009 ◽  
Vol 29 (9) ◽  
pp. 1517-1527 ◽  
Author(s):  
Henning Piilgaard ◽  
Martin Lauritzen
Keyword(s):  
Cortical Spreading Depression ◽  
Vascular Reactivity ◽  
Spreading Depression ◽  
Acute Hypoxia ◽  
Ion Homeostasis ◽  
Neurovascular Coupling ◽  
Doppler Flowmetry ◽  
Neurometabolic Coupling ◽  
Rat Neocortex ◽  
Cortical Electrical Activity

Cortical spreading depression (CSD) is associated with a dramatic failure of brain ion homeostasis and increased energy metabolism. There is strong clinical and experimental evidence to suggest that CSD is the mechanism of migraine, and involved in progressive neuronal injury in stroke and head trauma. Here we tested the hypothesis that single episodes of CSD induced acute hypoxia, and prolonged impairment of neurovascular and neurometabolic coupling. Cortical spreading depression was induced in rat frontal cortex, whereas cortical electrical activity and local field potentials (LFPs) were recorded by glass microelectrodes, cerebral blood flow (CBF) by laser—Doppler flowmetry, and tissue oxygen tension (tpO2) with Polarographic microelectrodes. Cortical spreading depression increased cerebral metabolic rate of oxygen (CMRO2) by 71% ± 6.7% and CBF by 238% ± 48.1% for 1 to 2 mins. For the following 2 h, basal tpO2 and CBF were reduced whereas basal CMRO2 was persistently elevated by 8.1% ± 2.9%. In addition, within first hour after CSD we found impaired neurovascular coupling (LFP versus CBF), whereas neurometabolic coupling (LFP versus CMRO2) remained unaffected. Impaired neurovascular coupling was explained by both reduced vascular reactivity and suppressed function of cortical inhibitory interneurons. The protracted effects of CSD on basal CMRO2 and neurovascular coupling may contribute to cellular dysfunction in patients with migraine and acutely injured cerebral cortex.

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