Simultaneous inhibition of TXA2 and PGI2 synthesis increases NO release in mesenteric resistance arteries from cirrhotic rats

2010 ◽  
Vol 119 (7) ◽  
pp. 283-292 ◽  
Author(s):  
Fabiano E. Xavier ◽  
Javier Blanco-Rivero ◽  
Esther Sastre ◽  
Lina Badimón ◽  
Gloria Balfagón
Keyword(s):  
Protein Expression ◽  
Resistance Arteries ◽  
Synthesis Inhibitor ◽  
Thromboxane A2 Receptor ◽  
Vasodilator Response ◽  
Cox Inhibitor ◽  
No Release ◽  
Simultaneous Inhibition ◽  
Cox 2 ◽  
Cox 1

Our present study examines, in mesenteric resistance arteries, possible vasodilation alterations, and the role of NO and COX (cyclo-oxygenase) derivatives, in cirrhosis. The vasodilator response to acetylcholine was analysed in segments from control and cirrhotic rats. The effects of the non-specific COX inhibitor indomethacin, the specific COX-1 inhibitor SC-560 and the specific COX-2 inhibitor NS-398 were analysed in segments from both groups of rats. NO release was measured, and eNOS [endothelial NOS (NO synthase)], phospho-eNOS, iNOS (inducible NOS), COX-1 and COX-2 protein expression was also analysed. The effects of the TP receptor [TXA2 (thromboxane A2) receptor] antagonist SQ 29548, the TXA2 synthesis inhibitor furegrelate, the PGI2 (prostaglandin I2) synthesis inhibitor TCP (tranylcypromine) or TCP+furegrelate were only determined in segments from cirrhotic rats. The vasodilator response to acetylcholine was higher in segments from cirrhotic rats. Indomethacin, SC-560 and NS-398 did not modify the vasodilator response in control rats; however, indomethacin, NS-398 and TCP+furegrelate increased, whereas SC-560 did not modify and SQ 29548, furegrelate or TCP decreased, the vasodilator response to acetylcholine in cirrhotic rats. NO release was higher in cirrhotic rats. Furegrelate decreased, whereas TCP+furegrelate increased, the NO release in segments from cirrhotic rats. eNOS and COX-1 protein expression was not modified, whereas phosho-eNOS, iNOS and COX-2 protein expression was higher in cirrhotic rats. Therefore the increase in iNOS expression and eNOS activity may mediate increases in endothelial NO release. The COX-2 derivatives TXA2 and PGI2 may act simultaneously, producing a compensatory effect that reduces NO release and may limit the hyperdynamic circulation.

Prostaglandins mediate tonic contraction of the guinea pig and human gallbladder

2007 ◽  
Vol 292 (1) ◽  
pp. G409-G418 ◽  
Author(s):  
Ping Cong ◽  
Zuo-Liang Xiao ◽  
Piero Biancani ◽  
Jose Behar
Keyword(s):  
Protein Expression ◽  
Tonic Contraction ◽  
Human Gallbladder ◽  
Small Interference Rna ◽  
Cox Inhibitors ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Dose Dependent Decrease ◽  
Dose Dependent ◽  
Cox 1

The gallbladder (GB) maintains tonic contraction modulated by neurohormonal inputs but generated by myogenic mechanisms. The aim of these studies was to examine the role of prostaglandins in the genesis of GB myogenic tension. Muscle strips and cells were treated with prostaglandin agonists, antagonists, cyclooxygenase (COX) inhibitors, and small interference RNA (siRNA). The results show that PGE2, thromboxane A2 (TxA2), and PGF2α cause a dose-dependent contraction of muscle strips and cells. However, only TxA2 and PGE2 (E prostanoid 1 receptor type) antagonists induced a dose-dependent decrease in tonic tension. A COX-1 inhibitor decreased partially the tonic contraction and TxB2 (TxA2 stable metabolite) levels; a COX-2 inhibitor lowered the tonic contraction partially and reduced PGE2 levels. Both inhibitors and the nonselective COX inhibitor indomethacin abolished the tonic contraction. Transfection of human GB muscle strips with COX-1 siRNA partially lowered the tonic contraction and reduced COX-1 protein expression and TxB2 levels; COX-2 siRNA also partially reduced the tonic contraction, the protein expression of COX-2, and PGE2. Stretching muscle strips by 1, 2, 3, and 4 g increased the active tension, TxB2, and PGE2 levels; a COX-1 inhibitor prevented the increase in tension and TxB2; and a COX-2 inhibitor inhibited the expected rise in tonic contraction and PGE2. Indomethacin blocked the rise in tension and TxB2 and PGE2 levels. We conclude that PGE2 generated by COX-2 and TxA2 generated by COX-1 contributes to the maintenance of GB tonic contraction and that variations in tonic contraction are associated with concomitant changes in PGE2 and TxA2 levels.

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.

scholarly journals Protection Effect of Self-Nanoemulsifying Drug Delivery System (SNEDDS) Piroxicam as Ulcerogenic Agent towards Malondialdehid Level and Protein Expression of Caspase-3, COX-1, COX-2 at Rat Gastric

2020 ◽  
pp. 273-283
Author(s):  
Iis Wahyuningsih ◽  
Kurnia Ambarwati ◽  
Erninda Ayu Hapsari ◽  
Afifah Fauziyyah ◽  
Azis Ikhsanudin ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Protein Expression ◽  
Drug Delivery System ◽  
Delivery System ◽  
Caspase 3 ◽  
Thiobarbituric Acid Reactive Substance ◽  
Sprague Dawley ◽  
Protection Effect ◽  
Cox 2 ◽  
Cox 1

The aim of this study was to determine the protection effect of SNEDDS piroxicam ulcerogenic agent against malondialdehyde (MDA) level and protein expression of caspase-3, COX-1, COX-2. The research was conducted using the test animals as much as 30 male white Sprague dawley (SD) rats aged 1-2 months with a weight of 100-200 grams divided into 5 groups. Treatment was given for 28 days orally. On the 29th day blood samples were also taken for the determination of MDA (Malondialdehid) levels by Thiobarbituric Acid Reactive Substance (TBARs) method using a visible spectrophotometer. Rats were sacrificed, then gastric organs were taken for immunohistochemical testing of caspase-3 and COX-1 expression, COX-2. The statistical analysis showed that the piroxicam SNEDDS group and the piroxicam suspension group decreased expression of the caspase-3 protein, increased COX-1 expression, decreased COX-2 and significantly decreased MDA levels. The piroxicam-containing SNEDDS (Self-Nanoemulsifying Drug Delivery System) form has protection against ulcogenic piroxicam.

scholarly journals The Characterization of Ground Raspberry Seeds and the Physiological Response to Supplementation in Hypertensive and Normotensive Rats

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1630
Author(s):  
Michał Majewski ◽  
Ewa Kucharczyk ◽  
Roman Kaliszan ◽  
Michał Markuszewski ◽  
Bartosz Fotschki ◽  
...  
Keyword(s):  
Essential Fatty Acids ◽  
Control Diet ◽  
Protective Role ◽  
Atherogenic Index ◽  
Control Group ◽  
Synthesis Inhibitor ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Wistar Kyoto ◽  
Main Component

This study aimed to evaluate the protective role of ground raspberry seeds (RBS) as a source of polyphenols and essential fatty acids on blood plasma enzymatic antioxidant status, lipid profile, and endothelium-intact vasodilation during physiological and pathological conditions. Young normotensive Wistar–Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) at ten weeks of age were fed with either a control diet or were supplemented with added 7% RBS for six weeks (n = 6). The main component of RBS was dietary fiber (64%) and the main polyphenols were ellagitannins (1.2%) and flavan-3-ols (0.45%). Irrespective of the rat model, ground RBS decreased liver enzyme aspartate aminotransferase (0.9-fold) and hydrogen peroxide scavenging capacity (Catalase, 0.9-fold). In supplemented SHRs, preincubation with inducible nitric oxide synthase (iNOS) inhibitor 1400W, nonselective cyclooxygenase (COX) inhibitor indomethacin, selective COX-2 inhibitor NS-398, prostacyclin (PGI2) synthesis inhibitor tranylcypromine (TCP), thromboxane receptor (TP) antagonist SQ-29548, thromboxane synthesis inhibitor furegrelate, and 20-HETE synthesis inhibitor HET0016 induced the same relaxant response to acetylcholine as in the nonsupplemented control group. In supplemented WKYs, atherogenic index was decreased (0.8-fold), while iNOS and COX-2-derived PGI2 increased acetylcholine-induced vasodilation. These effects of ground RBS may constitute a potential mechanism for preventing cardiovascular diseases.

scholarly journals Comparative Analysis of Pharmacologic and/or Genetic Disruption of Cyclooxygenase-1 and Cyclooxygenase-2 Function in Female Reproduction in Mice*

Endocrinology ◽  
2001 ◽  
Vol 142 (7) ◽  
pp. 3198-3206 ◽  
Author(s):  
Jeff Reese ◽  
Xuemei Zhao ◽  
Wen-Ge Ma ◽  
Naoko Brown ◽  
Timothy J. Maziasz ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Synergistic Effects ◽  
Female Reproduction ◽  
Cox Inhibitors ◽  
Cyclooxygenase 1 ◽  
Simultaneous Inhibition ◽  
Cox 2 ◽  
Alternative Sources ◽  
First Time ◽  
Cox 1

Abstract Cyclooxygenase (COX)-derived prostaglandins are critical in female reproduction. Gene targeting studies show that ovulation, fertilization, implantation, and decidualization are defective in COX-2 deficient mice. We used genetic and pharmacologic approaches to perturb COX function and examine the differential and synergistic effects of inhibition of COX-1, COX-2, or of both isoforms on reproductive outcomes during early pregnancy in mice. The results demonstrate that simultaneous inhibition of COX-1 and COX-2 produces more severe effects on early pregnancy events than inhibition of either isoform alone. The effects of pharmacological inhibition of COX-2 on female reproductive functions were less severe than the null mutation of the COX-2 gene. A combined approach showed that COX-2 inhibition in COX-1−/− mice induced complete reproductive failure, suggesting a lack of alternative sources of prostaglandin synthesis. This investigation raises caution regarding the indiscriminate use of COX inhibitors and shows for the first time the distinct and overlapping pathways of the cyclooxygenase systems in female reproduction.

scholarly journals Effects of Nonsteroidal Anti-Inflammatory Drugs onHelicobacter pylori-Infected Gastric Mucosae of Mice: Apoptosis, Cell Proliferation, and Inflammatory Activity

2001 ◽  
Vol 69 (8) ◽  
pp. 5056-5063 ◽  
Author(s):  
Tae Il Kim ◽  
Yong Chan Lee ◽  
Kwang Hyoung Lee ◽  
Jae Ho Han ◽  
Chae Yoon Chon ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cells ◽  
Protein Expression ◽  
Inflammatory Activity ◽  
Prostaglandin E ◽  
Gastric Epithelial Cells ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
H Pylori ◽  
Cox 1

ABSTRACT Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are two well-known important causative factors of gastric damage. While H. pylori increases apoptosis and the proliferation of gastric epithelial cells and is an important factor in peptic ulcer and gastric cancer, NSAIDs induce cell apoptosis and have antineoplastic effects. We investigated the effects of NSAIDs (a nonselective cyclooxygenase [COX] inhibitor [indomethacin] and a selective COX-2 inhibitor [NS-398]) on the apoptosis and proliferation of gastric epithelial cells and gastric inflammation inH. pylori-infected mice. C57BL/6 mice were sacrificed 8 weeks after H. pylori SS1 inoculation. Indomethacin (2 mg/kg) or NS-398 (10 mg/kg) was administered subcutaneously once daily for 10 days before sacrifice. The following were assessed: gastric inflammatory activity, gastric COX protein expression by Western blotting; gastric prostaglandin E2 levels by enzyme immunoassay, apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and cell proliferation by Ki67 immunostaining. Compared to the controls, H. pylori infection and/or NSAID treatment increased COX-1 and COX-2 protein expression. Gastric prostaglandin E2 levels, apoptotic index, cell proliferation index, neutrophil activity, and the degree of chronic inflammation were all increased by H. pylori infection, and these effects were significantly decreased by indomethacin treatment. However, NS-398 treatment after H. pylori infection did not induce a significant reduction, although it did result in a tendency to decrease. These results show that NSAIDs can reverse the increased apoptosis and proliferation of epithelial cells and inflammatory activity in the stomachs of H. pylori-infected mice and that, like COX-2 activation, COX-1 induction contributes to the change of gastric mucosal cell turnover and inflammation induced by H. pylori infection.

Key role for cyclooxygenase-2 in PGE2 and PGF2α receptor regulation and cerebral blood f low of the newborn

1997 ◽  
Vol 273 (4) ◽  
pp. R1283-R1290 ◽  
Author(s):  
Ding-You Li ◽  
Pierre Hardy ◽  
Daniel Abran ◽  
Ana-Katherine Martinez-Bermudez ◽  
Anne-Marie Guerguerian ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Receptor Agonist ◽  
Prostaglandin E ◽  
Receptor Density ◽  
Cerebral Vasculature ◽  
Newborn Brain ◽  
Cox Inhibitor ◽  
Newborn Pigs ◽  
Cox 2 ◽  
Cox 1

Ibuprofen, a cyclooxygenase (COX) inhibitor nonselective for either COX-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E2(PGE2) and PGF2α receptors in newborn pigs. COX-2 was shown to be the predominant form of COX and the main catalyst of prostaglandin synthesis in the newborn brain. We proceeded to establish direct evidence that COX-2-generated prostaglandins govern PGE2 and PGF2α receptor density and function in the cerebral vasculature of the newborn. Hence, we determined PGE2 and PGF2α receptor density and functions in brain vasculature by using newborn pigs treated with saline, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibitors (DUP-697 and NS-398). Newborn brain PGE2 and PGF2α concentrations were significantly reduced by ibuprofen, DUP-697, and NS-398 but not by valerylsalicylate. In newborn pigs treated with DUP-697, NS-398, and ibuprofen, PGE2 and PGF2α receptor densities in brain microvessels were increased to adult levels; there was also a significant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE2(EP1 receptor agonist), M&B-28767 (EP3 receptor agonist), PGF2α, and fenprostalene (PGF2αanalog). Treatment with ibuprofen or DUP-697 also increased the upper blood pressure limit of cerebral cortex and periventricular blood flow autoregulation from 85 to ≥125 mmHg (uppermost blood pressure studied). However, valerylsalicylate treatment did not affect cerebrovascular PGE2 and PGF2α receptors, IP3 production, or vasoconstrictor effects in newborn animals. These in vivo and in vitro observations indicate that COX-2 is mainly responsible for the regulation of PGE2 and PGF2α receptors and their functions in the newborn cerebral vasculature.

Endothelial COX-1 and -2 differentially affect reactivity of MVB in portal hypertensive rats

2002 ◽  
Vol 283 (3) ◽  
pp. G587-G594 ◽  
Author(s):  
M. A. Potenza ◽  
O. A. Botrugno ◽  
M. A. De Salvia ◽  
G. Lerro ◽  
C. Nacci ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Hypertensive Rats ◽  
Mesenteric Blood Flow ◽  
Western Blots ◽  
Vascular Bed ◽  
Cox Inhibitor ◽  
Mesenteric Vascular Bed ◽  
Cox 2 ◽  
Cox 1

Expression of constitutive and inducible cyclooxygenase (COX-1 and COX-2, respectively) and the role of prostanoids were investigated in the aorta and mesenteric vascular bed (MVB) from the portal vein-ligated rat (PVL) as a model of portal hypertension. Functional experiments were carried out in MVB from PVL and sham-operated rats in the absence or presence of the nonselective COX inhibitor indomethacin or the selective inhibitors of COX-1 (SC-560) or COX-2 (NS-398). Western blots of COX-1 and COX-2 proteins were evaluated in aorta and MVB, and PGI2 production by enzyme immunoassay of 6-keto-PGF1α was evaluated in the aorta. In the presence of functional endothelium, decreased contraction to norepinephrine (NE) and increased vasodilatation to ACh were observed in MVB from PVL. Exposure of MVB to indomethacin, SC-560, or NS-398 reversed the hyporeactivity to NE and the increased endothelial vasodilatation to ACh in PVL, with NS-398 being more potent than the other two inhibitors. Upregulation of COX-1 and COX-2 expressions was detected in aorta and MVB from PVL portal hypertensive rats, and increased production of 6-keto-PGF1α was observed in aorta from portal hypertensive rats. These results suggest that generation of endothelial vasodilator prostanoids, from COX-1 and COX-2 isoforms, accounts for the increased mesenteric blood flow in portal hypertension.

NO regulates LPS-stimulated cyclooxygenase gene expression and activity in pulmonary artery endothelium

2001 ◽  
Vol 280 (3) ◽  
pp. L450-L457 ◽  
Author(s):  
Jian-Xiong Chen ◽  
Leonard C. Berry ◽  
Brian W. Christman ◽  
Miles Tanner ◽  
Paul R. Myers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Gas Chromatography Mass Spectrometry ◽  
No Donors ◽  
Gene And Protein Expression ◽  
Cox 2 ◽  
Spermine Nonoate ◽  
Cox 1 ◽  
Expression And Activity

We examined whether nitric oxide (NO) inhibits prostanoid synthesis through actions on cyclooxygenase (COX) gene expression and activity. Bovine pulmonary artery endothelial cells were pretreated for 30 min with the NO donors 1 mM S-nitroso- N-acetylpenicillamine (SNAP), 0.5 mM sodium nitroprusside (SNP), or 0.2 μM spermine NONOate; controls included cells pretreated with either 1 mM N-acetyl-d-penicillamine or the NO synthase (NOS) inhibitor 1 mM N G-nitro-l-arginine methyl ester with and without addition of lipopolysaccharide (LPS; 0.1 μg/ml) for 8 h. COX-1 and COX-2 gene and protein expression were examined by RT-PCR and Western analysis, respectively; prostanoid measurements were made by gas chromatography-mass spectrometry, and COX activity was studied after a 30-min incubation with 30 μM arachidonic acid. LPS induced COX-2 gene and protein expression and caused an increase in COX activity and an eightfold increase in 6-keto-PGF1αrelease. LPS-stimulated COX-2 gene expression was decreased by ∼50% by the NO donors. In contrast, LPS caused a significant reduction in COX-1 gene expression and treatment with NO donors had little effect. SNAP, SNP, and NONOate significantly suppressed LPS-stimulated COX activity and 6-keto-PGF1α release. Our data indicate that increased generation of NO attenuates LPS-stimulated COX-2 gene expression and activity, whereas inhibition of endogenous NOS has little effect.

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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