Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

2008 ◽  
Vol 294 (1) ◽  
pp. H145-H155 ◽  
Author(s):  
Ting-Ting Hong ◽  
Jinbao Huang ◽  
Terrance D. Barrett ◽  
Benedict R. Lucchesi
Keyword(s):  
Coronary Artery ◽  
Vascular Reactivity ◽  
Thrombus Formation ◽  
Normal Coronary Artery ◽  
Cox Inhibitors ◽  
Inflammatory Conditions ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

This study was designed to determine the effect of inhibitors of cyclooxygenase (COX)-1, COX-2, and the nonselective COX inhibitor naproxen on coronary vasoactivity and thrombogenicity under baseline and lipopolysaccharide (LPS)-induced inflammatory conditions. We hypothesize that endothelial COX-1 is the primary COX isoform in the canine normal coronary artery, which mediates arachidonic acid (AA)-induced vasodilatation. However, COX-2 can be induced and overexpressed by inflammatory mediators and becomes the major local COX isoform responsible for the production of antithrombotic prostaglandins during systemic inflammation. The interventions included the selective COX-1 inhibitor SC-560 (0.3 mg/kg iv), the selective COX-2 inhibitor nimesulide (5 mg/kg iv), or the nonselective COX inhibitor naproxen (3 mg/kg iv). The selective prostacyclin (IP) receptor antagonist RO-3244794 (RO) was used as an investigational tool to delineate the role of prostacyclin (PGI2) in modulating vascular reactivity. AA-induced vasodilatation of the left circumflex coronary artery was suppressed to a similar extent by each of the COX inhibitors and RO. The data suggest that AA-induced vasodilatation in the normal coronary artery is mediated by a single COX isoform, the constitutive endothelial COX-1, which is reported to be susceptible to COX-2 inhibitors. The effect of the COX inhibitors on thrombus formation was evaluated in a model of carotid artery thrombosis secondary to electrolytic-induced vessel wall injury. Pretreatment with LPS (0.5 mg/kg iv) induced a systemic inflammatory response and prolonged the time-to-occlusive thrombus formation, which was reduced in the LPS-treated animals by the administration of nimesulide. In contrast, neither SC-560 nor naproxen influenced the time to thrombosis in the animals pretreated with LPS. The data are of significance in view of reported adverse cardiovascular events observed in clinical trials involving the use of selective COX-2 inhibitors, thereby suggesting that the endothelial constitutive COX-1 and the inducible vascular COX-2 serve important functions in maintaining vascular homeostasis.

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 Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

2008 ◽  
Vol 11 (2) ◽  
pp. 81 ◽  
Author(s):  
Praveen Rao ◽  
Edward E. Knaus
Keyword(s):  
Mechanism Of Action ◽  
Cardiovascular Effects ◽  
Nitric Oxide Donor ◽  
Structural Basis ◽  
Magic Bullet ◽  
Inflammatory Conditions ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors ◽  
Cox 1

Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. Methods. Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2 inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. Results. A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. Conclusions. A great deal of progress has been made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.

scholarly journals Cyclo-oxygenase-2 contributes to constitutive prostanoid production in rat kidney and brain

2005 ◽  
Vol 391 (3) ◽  
pp. 561-566 ◽  
Author(s):  
Pierre-Olivier Hétu ◽  
Denis Riendeau
Keyword(s):  
Rat Kidney ◽  
Significant Inhibition ◽  
Complete Analysis ◽  
Inflammatory Conditions ◽  
Prostanoid Production ◽  
Cox 2 ◽  
The Individual ◽  
Cox 2 Inhibitors ◽  
Cox 1 ◽  
Prostanoid Synthesis

Cyclo-oxygenases (COXs) catalyse the synthesis of PGH2 (prostaglandin H2), which serves as the common substrate for the production of PGE2, PGD2, PGF2α, prostacyclin (or PGI2) and TXs (thromboxanes). While COX-1 is the major isoform responsible for prostanoid synthesis in healthy tissues, little information is available on the contribution of constitutive COX-2 to the various prostanoid synthetic pathways under non-inflammatory conditions. To evaluate further the role of COX-2 in prostanoid biosynthesis, rats were acutely treated with the selective COX-1 inhibitor SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or the selective COX-2 inhibitors MF tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulphonyl)phenyl)-2-(5H)-furanone] and DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2-(5H)-furanone]. Selected tissues were then processed for a complete analysis of their prostanoid content by liquid chromatography MS. Whereas the treatment with SC-560 caused a 60–70% inhibition in the total prostanoid content of most tissues examined, a significant decrease (35–50%) in total prostanoid content following selective COX-2 inhibition was solely detected for kidney and brain tissues. Analysis of the individual prostanoids reveals significant inhibition of 6-oxo-PGF1α, PGE2, PGD2, PGF2α and TXB2 in the kidney and inhibition of all these prostanoids with the exception of PGD2 in the forebrain. These results demonstrate that constitutively expressed COX-2 contributes to the production of prostanoids in kidney and brain for each of the PGE2, PGI2 and TXB2 pathways under non-inflammatory conditions. Approaches to modulate inflammation through specific inhibition of terminal synthases, such as mPGES-1 (microsomal PGE2 synthase-1), thus have the potential to differ from COX-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs with regard to effects on constitutive prostanoid synthesis and on renal function.

Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo

2000 ◽  
Vol 278 (6) ◽  
pp. R1496-R1505 ◽  
Author(s):  
Yasushi Takahashi ◽  
Christine Roman ◽  
Sylvain Chemtob ◽  
Mary M. Tse ◽  
Emil Lin ◽  
...  
Keyword(s):  
Ductus Arteriosus ◽  
Plasma Concentrations ◽  
Additional Increase ◽  
Cox Inhibitors ◽  
Fetal Plasma ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE2 and 6ketoPGF1α production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 ± 0.6 μg/ml, mean ± standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE2 and 6ketoPGF1α. Indomethacin (0.7 ± 0.2 μg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.

scholarly journals Synthesis and theoretical activity evaluation of a new steroid-oxazolone derivative against COX1-1 and COX-2

2019 ◽  
Vol 9 (4) ◽  
pp. 4107-4113
Keyword(s):  
Elemental Analysis ◽  
Cox Inhibitors ◽  
Activity Evaluation ◽  
Docking Model ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Cox 1

There are some reports for the preparation of several drugs as cyclooxygenase (COX) inhibitors; however, some reagents used in the preparation are expensive and difficult to handle. The aim of this study was to synthesize a steroid-oxazolone derivativeusing some reactions such as i) hydroxylation-amiination; ii) amidation; iii) alkynyl-addition; iv) aldolization and iv) imination. In addition, a theoretical ass was carried out to evaluate the interaction of both COX-1 and COX-2 with the steroid-oxazolone derivativeusing indomethacin and rofecoxib as controls in a docking model. The structure of the compounds obtained was confirmed through elemental analysis, spectroscopy and spectrometry data. The results showed that there are differences between the interaction of the steroidoxazolone derivativewith both COX 1 and COX 2 compared with the bound of indomethacin and rofecoxib with this type of enzymes. These data suggest that the steroid-oxazolone derivativecould be a good candidate as COX-inhibitor translated as a possible drug for treatment of pain.

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.

Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits

2009 ◽  
Vol 297 (5) ◽  
pp. H1882-H1888 ◽  
Author(s):  
Nabil Foudi ◽  
Xavier Norel ◽  
Mario Rienzo ◽  
Liliane Louedec ◽  
Charles Brink ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Abdominal Aorta ◽  
Vascular Reactivity ◽  
Prostaglandin E ◽  
Organ Bath ◽  
Cox Inhibitors ◽  
Atherosclerotic Lesions ◽  
Cox 2 ◽  
Atherosclerotic Process ◽  
Cox 2 Inhibitors

Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 μmol/l) and indomethacin (1.7 μmol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I2 but not of prostaglandin E2, prostaglandin D2, or thromboxane A2 in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I2 release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions.

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.

Aging associated with mild dyslipidemia reveals that COX-2 preserves dilation despite endothelial dysfunction

2007 ◽  
Vol 292 (1) ◽  
pp. H451-H458 ◽  
Author(s):  
Marie-Ève Gendron ◽  
Nathalie Thorin-Trescases ◽  
Louis Villeneuve ◽  
Eric Thorin
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Endothelial Damage ◽  
Wild Type ◽  
Cox Inhibitors ◽  
The Face ◽  
Vascular Sensitivity ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

The endothelial function declines with age, and dyslipidemia (DL) has been shown to hasten this process by favoring the generation of reactive oxygen species (ROS). Cyclooxygenase-2 (COX-2) can be induced by ROS, but its contribution to the regulation of the endothelial function is unknown. Since COX-2 inhibitors may be deleterious to the cardiovascular system, we hypothesized that DL leads to ROS-dependent endothelial damage and a protective upregulation of COX-2. Dilations to acetylcholine (ACh) of renal arteries isolated from 3-, 6-, and 12-mo-old wild-type (WT) and DL mice expressing the human ApoB-100 were recorded with or without COX inhibitors and the antioxidant N-acetyl-l-cystein (NAC). Nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) were inhibited using Nω-nitro-l-arginine (l-NNA) and a depolarizing solution, respectively. In WT mice, the dilation to ACh declined at 12 mo but was insensitive to COX-1/2 inhibition alone or with NAC. DL led to an early endothelial dysfunction at 6 mo, normalized, however, by NAC. At 12 mo, vascular sensitivity to ACh was further reduced by DL. At this age, selective COX-2 inhibition reduced the dilation, whereas addition of NAC improved it. In 3- and 6-mo-old WT mice, l-NNA significantly reduced the dilation, whereas it limited the dilation only in 3-mo-old DL mice. EDHF-dependent dilation remains identical in both groups. These data suggest that COX-2 activity confers endothelium-dependent vasodilatory function in aged DL mice in the face of a pro-oxidative environment. Upregulation of this pathway compensates for the early loss of the contribution of NO in DL mice.

COX-2-dependent and potentially cardioprotective effects of negative inotropic substances released after ischemia

2007 ◽  
Vol 293 (4) ◽  
pp. H2148-H2154 ◽  
Author(s):  
Katrin Birkenmeier ◽  
Alexander Staudt ◽  
Wolf-Hagen Schunck ◽  
Irka Janke ◽  
Corina Labitzke ◽  
...  
Keyword(s):  
Fluorescence Microscopy ◽  
Negative Inotropic Effect ◽  
Rat Cardiomyocytes ◽  
Cell Shortening ◽  
Rat Hearts ◽  
Cox Inhibitor ◽  
Cardioprotective Effects ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

During reperfusion, cardiodepressive factors are released from isolated rat hearts after ischemia. The present study analyzes the mechanisms by which these substances mediate their cardiodepressive effect. After 10 min of global stop-flow ischemia, rat hearts were reperfused and coronary effluent was collected over a period of 30 s. We tested the effect of this postischemic effluent on systolic cell shortening and Ca2+ metabolism by application of fluorescence microscopy of field-stimulated rat cardiomyocytes stained with fura-2 AM. Cells were preincubated with various inhibitors, e.g., the cyclooxygenase (COX) inhibitor indomethacin, the COX-2 inhibitors NS-398 and lumiracoxib, the COX-1 inhibitor SC-560, and the potassium (ATP) channel blocker glibenclamide. Lysates of cardiomyocytes and extracts from whole rat hearts were tested for expression of COX-2 with Western blot analysis. As a result, in contrast to nonischemic effluent (control), postischemic effluent induced a reduction of Ca2+ transient and systolic cell shortening in the rat cardiomyocytes ( P < 0.001 vs. control). After preincubation of cells with indomethacin, NS-398, and lumiracoxib, the negative inotropic effect was attenuated. SC-560 did not influence the effect of postischemic effluent. The inducibly expressed COX-2 was detected in cardiomyocytes prepared for fluorescence microscopy. The effect of postischemic effluent was eliminated with applications of glibenclamide. Furthermore, postischemic effluent significantly reduced the intracellular diastolic and systolic Ca2+ increase ( P < 0.01 vs. control). In conclusion, the cardiodepressive effect of postischemic effluent is COX-2 dependent and protective against Ca2+ overload in the cells.

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