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PubMed1997

Comparison of the nitric oxide and cyclo-oxygenase pathway in mesenteric resistance vessels of normotensive and spontaneously hypertensive rats.

1. The double perfused mesentery was used to compare arterial and venous KCl- and acetylcholine (ACh)-induced responses in tissues taken from normotensive (WKY) and spontaneously hypertensive rats (SHR) in the presence or absence of inhibitors of nitric oxide (NO) synthase (NG-nitro-L-arginine (L-NOARG) and NG-nitro-L-arginine methyl ester (L-NAME)) and cyclo-oxygenase (indomethacin, mefenamic acid). 2. KCl (20 to 120 mM K+) caused concentration-dependent increases in arterial and venous perfusion pressures. The maximal arterial effects were significantly higher in the SHRs than in the WKY, with no differences in the venous pressor responses. 3. L-NAME and L-NOARG (100 microM) had no effect on the basal perfusion pressures in tissues from either WKY or SHRs, and mefenamic acid only induced a significant reduction of the basal perfusion pressures in the venous mesenteric vessels isolated from WKY. 4. L-NAME and L-NOARG (100 microM) potentiated the pressor responses to KCl to the same extent in the venous and arterial beds derived from WKY and SHR, while indomethacin and mefenamic acid (5 microM) only significantly decreased these responses in WKY. 5. Acetylcholine (ACh)-induced relaxations (1 nM to 10 microM) were significantly higher in arterial beds of WKY than in SHR, without differences in the venous relaxant responses. 6. L-NAME (100 microM) inhibited ACh-induced relaxations in arterial and venous beds from both groups of rats. Mefenamic acid was without effect on ACh-induced relaxations in either the arterial or the venous beds from WKY and SHR. 7. In conclusion, the liberation of NO in the perfused mesenteric vasculatures requires an active tone and no dysfunction of NO synthase activity is functionally apparent in the mesenteries isolated from SHRs. The cyclo-oxygenase pathway is only implicated in the KCl-induced responses of tissues derived from WKY, but not in the vasodilatations induced by ACh in either the arterial or the venous vasculatures from WKY and SHR.

Acetylcholine↗
PubMed1998

Enhancement of opioid inhibition of GABAergic synaptic transmission by cyclo-oxygenase inhibitors in rat periaqueductal grey neurones.

Cyclo-oxygenase (COX) inhibitors potentiate opioid inhibition of GABAergic synaptic transmission in rat periaqueductal grey (PAG) (Vaughan et al., 1997). In the present study, the relative contribution of cyclo-oxygenase-1 (COX-1) and COX-2 inhibition to this phenomenon was examined by use of whole-cell patch clamp recordings in brain slices. The mu-receptor partial agonist morphine (10 microM) had little effect on GABAergic synaptic transmission. Morphine reduced the frequency of spontaneous miniature inhibitory postsynaptic currents (m.i.p.s.cs) by 13%. The nonselective COX inhibitor, indomethacin, produced a dose-dependent potentiation of the morpine inhibition of m.i.p.s.c. frequency (maximum inhibition 42%, IC50=6 nM). More selective COX-2 inhibitors produced a similar potentiation of the morphine inhibition of m.i.p.s.c. frequency; however, at greater concentrations (IC50=57 nM piroxicam, 1.7 microM DFU). Maintaining slices in the protein synthesis inhibitor cycloheximide (1 microM), to prevent COX-2 induction, had no effect on the potentiation action of DFU (10 microM). These results demonstrate that the potentiation of opioid inhibition of GABAergic synaptic transmission in PAG is largely a result of inhibition of COX-1 activity. These findings suggest that COX-1, rather than COX-2 inhibition, mediates the synergistic analgesic actions of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in the midbrain PAG.

Analgesics, Opioid↗
PubMed1998

Effects of inhibitors of the activity of cyclo-oxygenase-2 on the hypotension and multiple organ dysfunction caused by endotoxin: a comparison with dexamethasone.

1. Endotoxaemia is associated with the expression of the inducible isoform of cyclo-oxygenase, cyclo-oxygenase-2 (COX-2), and an overproduction of arachidonic acid (AA) metabolites. The role of the AA metabolites generated by COX-2 in the circulatory failure and multiple organ dysfunction caused by endotoxin is unclear. Dexamethasone prevents the expression of COX-2 and exerts beneficial effects in animal models of shock. 2. Here we compare the effects of two inhibitors of COX-2 activity, namely NS-398 (5 mg kg(-1), i.p., n=7) and SC-58635 (3 mg kg(-1), i.p., n=9) with those of dexamethasone (3 mg kg(-1), i.p., n=9) on the circulatory failure and organ dysfunction caused by lipopolysaccharide (LPS, E. coli, 6 mg kg(-1), i.v., n=11) in the rat. 3. Endotoxaemia for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6-keto-PGF1alpha (indicator of the induction of COX-2) and nitrite/nitrate (indicator of the induction of iNOS). 4. Pretreatment of rats with dexamethasone attenuated the hypotension, the renal dysfunction, the hepatocellular and pancreatic injury and the induction of COX-2 and iNOS caused by LPS. In contrast, inhibition of COX-2 activity with SC-58635 or NS-398 neither attenuated the circulatory failure nor the multiple organ failure caused by endotoxin. 5. Thus, the prevention of the circulatory failure and the multiple organ injury/dysfunction caused by dexamethasone in the rat is not due to inhibition of the activity of COX-2. Our results suggest that an enhanced formation of eicosanoids by COX-2 does not contribute to the development of organ injury and/or dysfunction in rats with endotoxaemia.

6-Ketoprostaglandin F1 alpha↗
PubMed2002

Selective inhibitors of cyclo-oxygenase-2 (COX-2) induce hypoalgesia in a rat paw model of inflammation.

1. It is well-established that inhibitors of cyclo-oxygenase (COX) and hence of prostaglandin (PG) biosynthesis reverse inflammatory hyperalgesia and oedema in both human and animal models of inflammatory pain. 2. Paw oedema and hyperalgesia in rats were induced by injecting carrageenan (250 micro g paw(-1)) into a hindpaw. Both inflammatory responses were followed for 24 h after the injection, measuring hyperalgesia by decreased pain threshold in the paws and oedema by plethysmography. 3. Three selective inhibitors of cyclo-oxygenase-2 (COX-2), celecoxib, rofecoxib and SC 236, given systemically in a range of doses, before the inflammatory stimulus, abolished carrageenan-induced hyperalgesia with little reduction of oedema. These inhibitors also induced hypoalgesia, increasing nociceptive thresholds in the inflamed paw above normal, non-inflamed levels. This hypoalgesia was lost at the higher doses of the selective inhibitors, although hyperalgesia was still prevented. 4. In paws injected with saline only, celecoxib, given at the dose inducing the maximum hypoalgesia after carrageenan, did not alter the nociceptive thresholds. 5. Two non-selective inhibitors of COX-2, indomethacin and piroxicam, abolished hyperalgesia and reduced oedema but did not induce hypoalgesia. 6. Celecoxib given locally into the paw also abolished inflammatory hyperalgesia and induced hypoalgesia without reducing oedema. 7. We conclude that hypoalgesia is expressed only over a critical range of COX-2 inhibition and that concomitant inhibition of COX-1 prevents expression of hypoalgesia, although hyperalgesia is still prevented. 8 Our results suggest a novel anti-nociceptive pathway mediating hypoalgesia, involving COX-2 selectively and having a clear peripheral component. This peripheral component can be further explored for therapeutic purposes.

Animals↗
PubMed2002

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-beta(1)-dependent pathway.

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and prostaglandin synthesis. Identification of molecular targets regulated by COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor SC-236 on gastric cancer. We showed that SC-236 induced apoptosis in gastric cancer cells. However, this effect was not dependent on COX-2 inhibition. SC-236 down-regulated the protein expression and kinase activity of PKC-beta(1), increased the expression of PKCdelta and PKCeta, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE(2) receptor antagonists could not reverse the inhibition effect on PKCbeta(1) by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCbeta(1) attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21(waf1/cip1). Inhibition of PKCbeta(1)-mediated overexpression of p21(waf1/cip1) partially reduced the anti-apoptotic effect of PKCbeta(1). The down-regulation of PKCbeta(1) provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCbeta(1) act as survival mediator in gastric cancer, and its down-regulation by COX-2 inhibitor SC-236 may provide new target for future treatment of gastric cancer.

Apoptosis↗
PubMed2004

Cyclo-oxygenase type 2-dependent prostaglandin E2 secretion is involved in retrovirus-induced T-cell dysfunction in mice.

MAIDS (murine AIDS) is caused by infection with the murine leukaemia retrovirus RadLV-Rs and is characterized by a severe immunodeficiency and T-cell anergy combined with a lymphoproliferative disease affecting both B- and T-cells. Hyperactivation of the cAMP-protein kinase A pathway is involved in the T-cell dysfunction of MAIDS and HIV by inhibiting T-cell activation through the T-cell receptor. In the present study, we show that MAIDS involves a strong and selective up-regulation of cyclo-oxygenase type 2 in the CD11b+ subpopulation of T- and B-cells of the lymph nodes, leading to increased levels of PGE2 (prostaglandin E2). PGE2 activates the cAMP pathway through G-protein-coupled receptors. Treatment with cyclo-oxygenase type 2 inhibitors reduces the level of PGE2 and thereby reverses the T-cell anergy, restores the T-cell immune function and ameliorates the lymphoproliferative disease.

Animals↗
PubMed1987

Modulation by pterins of the phosphorylation and phenylalanine activation of phenylalanine 4-mono-oxygenase.

The interaction between phenylalanine 4-mono-oxygenase and analogues of the natural cofactor (6R)-tetrahydrobiopterin [(6R)-BH4] was studied. The rate of cyclic AMP-dependent phosphorylation of phenylalanine 4-mono-oxygenase was inhibited only by those pterins [(6R)-BH4, (6S)-BH4 and 7,8-dihydrobiopterin (BH2)] that were able to decrease the potency and efficiency of phenylalanine as an allosteric activator of the hydroxylase. Since BH2 lacks cofactor activity, this was not required to modulate either the phosphorylation or the phenylalanine-activation of the hydroxylase. Half-maximal inhibition of the phosphorylation was observed at 1.9 microM-(6R)-BH4, 9 microM-(6S)-BH4 and 17 microM-BH2. Competition experiments indicated that all three pterins acted through binding to the cofactor site of the hydroxylase. Since the phosphorylation site and the cofactor binding site are known to reside, respectively, in the N- and C-terminal domains of the hydroxylase, the pterins were able to induce an interdomain conformational change. BH2, whose dihydroxypropyl group is not subject to epimerization, and (6S)-BH4 both inhibited the phosphorylation less efficiently than did the (6R)-epimer of BH4. Pterins with different spatial arrangements of the dihydroxypropyl side chain thus appeared to elicit different conformations of the phosphorylation site. The hydroxylase reaction showed a higher apparent Km for (6S)-BH4 than for (6R)-BH4 both when the native and the phenylalanine-activated enzyme were tested. For the activated enzyme Vmax was 40% lower with the (6S)-epimer than the (6R)-epimer, also when the more rapid enzyme inactivation occurring with the former cofactor was taken into account.

Binding Sites↗
PubMed1988

Isolation of pure anhydrotetracycline oxygenase from Streptomyces aureofaciens.

Anhydrotetracycline oxygenase was purified to homogeneity from Streptomyces aureofaciens, a producer of tetracycline. The enzyme was purified 60-fold in a 40% yield by a two-step procedure using a combination of hydrophobic chromatography and ion-exchange h.p.l.c. Purified anhydrotetracycline oxygenase was homogeneous according to SDS/polyacrylamide-gel electrophoresis, isoelectric focusing, ion-exchange h.p.l.c. on a Mono Q HR 5/5 column and size-exclusion h.p.l.c. on a TSK G 3000 SW column. The enzyme consists of two subunits of Mr 57,500, as determined by SDS/polyacrylamide-gel electrophoresis.

Chromatography, High Pressure Liquid↗
PubMed1995

Involvement of tyrosine kinases in the induction of cyclo-oxygenase-2 in human endothelial cells.

In addition to a constitutive cyclo-oxygenase (Cox-1), human endothelial cells also possess an inducible cyclo-oxygenase (Cox-2) which plays an important role in the regulation of the synthesis of prostacyclin (prostaglandin I2). Cox-2 is regulated and expressed in large quantities upon activation of the cells by inducers such as phorbol myristate acetate (PMA), an activator of protein kinase C (PKC), or interleukin-1 alpha. We have investigated the involvement of protein tyrosine kinases in Cox-2 expression by human endothelial cells upon activation by these inducers. PMA or interleukin-1 alpha provoke an increase in the phosphorylation of substrates of 110 and 120 kDa and additional phosphorylations for a broad band of multiple substrates in the 70 kDa range. This stimulation was accompanied by the induction of Cox-2 protein, detectable after stimulation for 1 h, which is consistent with an increase in activity reflected by prostacyclin synthesis; no variation in the expression of Cox-1 could be observed. Three distinct inhibitors of protein tyrosine kinases, genistein, herbimycin or AG-213, reduced tyrosine phosphorylation of cell substrates, consistently with their pharmacological effects. Under these conditions, there was selective reduction of Cox-2 expression without modification of Cox-1. Regulation of Cox-2 induction is also dependent on the activation of PKC since Ro 31-8220 or PKC depletion by PMA prevented its induction. Our results suggest that within the time-frame of our experiments these effects on kinases are specific for Cox-2 rather than Cox-1.

Benzoquinones↗
PubMed1996

Comparative study of the effects of nitric oxide synthase and cyclo-oxygenase inhibition on duodenal functions in rats anaesthetized with inactin, urethane or alpha-chloralose.

This study was undertaken to investigate the effects of a cyclo-oxygenase and a nitric oxide synthase (NOS) inhibitor on duodenal mucosal alkaline secretion (DMAS), motility and mucosal permeability in inactin-, urethane- and alpha-chloralose anaesthetized rats. Proximal duodenum was perfused with a 150 mM NaCl solution and DMAS was determined by back titration. Mucosal permeability was assessed by measuring blood to lumen clearance of 51Cr-EDTA and duodenal motility by measuring intraluminal pressure. Mean arterial blood pressure and mucosal permeability were significantly lower in urethane- than in inactin- or alpha-chloralose anaesthetized rats (urethane: 90 +/- 2 mm Hg and 0.15 +/- 0.02 mL min-1 100 g-1; inactin: 112 +/- 5 mm Hg and 0.62 +/- 0.15 mL min-1 100 g-1; alpha-chloralose: 111 +/- 4 mm Hg and 0.61 +/- 0.06 mL min-1 100 g-1, respectively). Basal (pre-drug) DMAS was significantly lower in urethane rats (6.2 +/- 1.0 mumol cm-1 h-1) than in alpha-chloralose (9.3 +/- 1.2 mumol cm-1 h-1), but not different from that in inactin-anaesthetized rats (7.5 +/- 0.8 mumol cm-1 h-1). No or very few spontaneous duodenal contractions occurred under the control (pre-drug) conditions in any group. All animals responded to the cyclo-oxygenase inhibitor indomethacin or the NOS inhibitor N-nitro-L-arginine-methyl-ester (L-NAME) with induction of duodenal motility and an increase in DMAS. The effect of indomethacin or L-NAME on mucosal permeability was similar in all anaesthetic groups except that L-NAME induced a transient increase in the inactin and alpha-chloralose groups but a sustained increase in urethane-anaesthetized animals. It is concluded that inactin- and alpha-chloralose anaesthetized rats do not differ regarding the studied basal values. Urethane-anaesthetized animals differed from rats given the other two anaesthetics in that basal mucosal permeability and mean arterial blood pressure were lower. Endogenous prostaglandins and NO contribute to the postoperative ileus and the low rate of DMAS also in urethane- and alpha-chloralose.

Anesthesia, General↗
PubMed1997

Aspirin causes rapid up-regulation of cyclo-oxygenase-2 expression in the stomach of rats.

BACKGROUND: Cyclo-oxygenase-1 (COX-1) is believed to produce prostaglandins vital to mucosal defence, whereas cyclo-oxygenase-2 (COX-2) is induced at sites of inflammation. Little is known about the regulation of COX-2 in the stomach, particularly during the period following mucosal injury. In this study, we examined COX-1 and COX-2 expression shortly after administration of NSAIDs or ethanol. METHODS: Fasted rats were given aspirin, salicylate, indomethacin or ethanol (20% or 40%) orally. Three hours later the stomach was excised, the severity of damage scored and samples taken for RT-PCR of COX-1 and COX-2 mRNA and immunohistochemistry. Nitric oxide synthase mRNA (iNOS and eNOS) and activity were also measured. RESULTS: Aspirin, indomethacin and the higher concentration of ethanol produced widespread mucosal damage, whereas salicylate and 20% ethanol caused only superficial epithelial damage. Aspirin caused a significant increase in COX-2 mRNA expression and a marked increase in COX-2 immunoreactivity, particularly in the superficial mucosa. Expression of COX-1 (mRNA and protein) was unaffected by aspirin, as were NOS mRNA expression and enzyme activity. Pre-treatment with prostaglandin E2 prevented the induction of COX-2 by aspirin. Salicylate and indomethacin caused modest increases in COX-2 immunoreactivity but no change in COX-2 mRNA. Neither concentration of ethanol affected COX-2 mRNA or protein expression, suggesting that this was a specific response to the aspirin, rather than to injury. CONCLUSIONS: These results demonstrate a rapid up-regulation of COX-2 expression in response to aspirin, possibly representing a compensatory response to inhibition of gastric prostaglandin synthesis.

Animals↗
PubMed2003

Review article: The pharmacological properties and clinical use of valdecoxib, a new cyclo-oxygenase-2-selective inhibitor.

Cyclo-oxygenase-2-selective inhibitors produce less gastric damage than conventional non-steroidal anti-inflammatory drugs. Valdecoxib is a new orally administered cyclo-oxygenase-2-selective inhibitor, recently approved for use in osteoarthritis, rheumatoid arthritis and primary dysmenorrhoea in the USA. The drug has been evaluated in more than 60 clinical studies involving more than 14 000 patients and healthy volunteers. The analgesic efficacy of valdecoxib at a dose of 10 mg once daily in both osteoarthritis and rheumatoid arthritis is superior to that of placebo and similar to that of traditional non-steroidal anti-inflammatory drugs. Valdecoxib is effective in single doses of up to 40 mg for the alleviation of acute menstrual pain and has a rapid onset of action (within 30 min) and a long duration of analgesia (up to 24 h). Valdecoxib is well tolerated and has safety advantages compared with traditional non-steroidal anti-inflammatory drugs in terms of less gastrointestinal toxicity and a lack of an effect on platelet function. The incidence of adverse effects involving the kidney (fluid retention, oedema and hypertension) is similar to that of non-selective, non-steroidal anti-inflammatory drugs.

Adult↗
PubMed2003

An open-label trial of the selective cyclo-oxygenase-2 inhibitor, rofecoxib, in inflammatory bowel disease-associated peripheral arthritis and arthralgia.

BACKGROUND: Conventional non-steroidal anti-inflammatory drugs have been associated with an increased risk of exacerbation of inflammatory bowel disease. AIM: To evaluate, in a prospective, open-label study, the safety and efficacy of a 20-day regimen of the selective cyclo-oxygenase-2 inhibitor, rofecoxib, 12.5-25 mg/day, in inflammatory bowel disease patients with associated peripheral arthropathy and/or arthritis. METHODS: Patients with clinically inactive to mild inflammatory bowel disease and a joint pain score of at least two points on a scale ranging from zero (none) to four (very poor) were eligible. Response was defined by a decrease of at least two points in the arthralgia score. RESULTS: Of the 32 patients included, 26 (81%) were treated with rofecoxib, 25 mg/day, and six (19%) with rofecoxib, 12.5 mg/day. In three patients (9%), rofecoxib had to be withdrawn after a few days due to gastrointestinal complaints which ceased immediately after drug discontinuation. No flare of inflammatory bowel disease occurred. Thirteen of the 32 patients (41%) were responders and, overall, the arthralgia score decreased from two to one (P = 0.0001). CONCLUSIONS: This is the first prospective study on the use of a selective cyclo-oxygenase-2 inhibitor in inflammatory bowel disease patients with peripheral arthropathy and/or arthralgia. The promising safety and efficacy profile warrants further evaluation in controlled trials.

Adult↗
PubMed1998

Expression of cyclo-oxygenase 1 and 2 proteins in upper respiratory mucosa.

BACKGROUND: Cyclo-oxygenases 1 (Cox-1) and 2 (Cox-2) catalyse the conversion of arachidonic acid to prostaglandin endoperoxides, leading to the formation of prostaglandin and thromboxane mediators of inflammation. The involvement of these enzymes in inflammatory disorders such as sinusitis and nasal polyps is unknown although this may be relevant to their pathophysiology. METHODS: We studied Cox-1 and Cox-2 immunoreactivities in nasal polyp, maxillary sinus, and turbinate biopsies obtained from eight patients with chronic allergic rhinitis and sinusitis and/or nasal polyps, 15 patients with chronic non-allergic rhinitis and sinusitis and/or nasal polyps and five control subjects (patients requiring nose surgery not related to sinusitis or nasal polyps). RESULTS: Both Cox- and Cox-2 were mainly expressed in the epithelium (basal, ciliated) and were found in 16/28 and 25/28 subjects for Cox-1 and Cox-2 respectively. We did not find any differences between the patient populations. There were no correlations between any of the clinical parameters studied nor the pathological patterns and the presence and characteristics of the Cox immunoreactivities. CONCLUSION: Both cyclo-oxygenase enzymes are expressed in normal human upper respiratory epithelium and are not upregulated in chronic sinusitis nor in nasal polyposis, possibly suggesting that Cox products do not have an important role as mediators of the chronic upper airway inflammation.

Adolescent↗
PubMed1996

Two mechanisms for platelet-mediated killing of tumour cells: one cyclo-oxygenase dependent and the other nitric oxide dependent.

We have tried to identify the cytotoxic effectors in platelet-mediated tumour cell killing, using two tumour cell lines K562 (a chronic myelogenic leukaemic cell line) and LU99A (a lung cancer cell line), which are both sensitive to platelet cytotoxicity. Cyclo-oxygenase inhibitors, acetylsalicylic acid (ASA) and indomethacin, effectively inhibited the platelet-mediated killing of K562 cells, but not that of LU99A cells. In contrast, inhibitors of the nitric oxide (NO) pathway. NG-nitro-1-arginine (L-NA), haemoglobin and methylene blue, reduced the cytotoxic activity of platelets against LU99A, but not against K562. Synthetic analogues of platelet cyclo-oxygenase products thromboxane A2/ prostaglandin H2(TXA2/PGH2) exerted cytotoxicity against K562 cells but not against LU99A cells. Electron microscopic study showed that TXA2/PGH2 analogues induced bleb formation and disruption of the plasma membrane of K562 cells. K562 cells enhanced the production of TXA2 by platelets, as inferred from the accumulation of thromboxane B2 (TXB2), a spontaneous hydrolysis product of TXA2. LU99A cells had no such effects. These results indicate that platelets kill these two tumour cell lines through different mechanisms. In K562, the cyclooxygenase products TXA2/PGH2 possibly play a significant role but in LU99A the NO pathway seems to be involved.

Aspirin↗
PubMed2000

Effects of the inhibition of cyclo-oxygenase 1 or 2 or 5-lipoxygenase on the activation of the hypothalamic-pituitary-adrenal axis induced by interleukin-1beta in the male Rat.

The limited entry of interleukin-1beta (IL-1beta) into the central nervous system has led to the hypothesis that IL-1beta acts, through IL-1beta receptors located notably on endothelial cells, on the release of prostaglandins which in turn stimulate the hypothalamic-pituitary-adrenal (HPA) axis. We used cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors, before the injection of IL-1beta, to explore the role of arachidonic acid metabolic pathways on HPA axis activation. Adult male rats were i.m injected 20 min before i.p injection of IL-1beta, with (i): a COX-1/COX-2 inhibitor (ketoprofen); (ii) a COX-2 selective inhibitor (NS 398); or (iii) a 5-LOX inhibitor (BW A4C). Following this, rats were killed 90 min after i.p. IL-1beta injection and analysis for plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations and determination of anterior pituitary pro-opio melanocortin (POMC) gene transcription was conducted. Administration of the COX-1/COX-2 inhibitor led to a complete blockage of ACTH and corticosterone secretion and POMC gene transcription. The COX-2 inhibitor led to a complete blockade of ACTH secretion and POMC gene transcription but had no effect on corticosterone secretion. The 5-LOX inhibitor had no significant effect on any parameter. These results demonstrate the crucial role of eicosanoid pathways in mediating the stimulation of the HPA axis induced by IL-1beta. Moreover, we found a clear dissociation of the effect of the blockage of COXs upon ACTH and corticosterone secretion, suggesting that IL-1beta may act at the brain as well as at the adrenal cortex to stimulate the secretion of corticosterone.

Adrenocorticotropic Hormone↗
PubMed2001

Regulation of cyclo-oxygenase-2.

Over the past three decades studies have been conducted to determine the role of prostaglandins in normal physiology and in certain diseases. Cyclo-oxygenase (COX) or prostaglandin endoperoxide synthase (Pghs) is required for the conversion of arachidonic acid to prostaglandins. Two isoforms of this enzyme have been identified which are referred to as COX-1 and COX-2. Under most circumstances, COX-1 is produced constitutively, whereas COX-2 can be induced by several physiological stimuli and is expressed at sites of inflammation. Although these isozymes catalyze identical reactions, they are often regulated by different signalling systems. The goal of this chapter is to provide a review of the role of cyclo-oxygenase in biology and disease, and to summarize the current understanding of mechanisms for the regulation of COX-2 expression.

Arachidonic Acid↗
PubMed2003

The effects of a cyclo-oxygenase II inhibitor on placental artery production of thromboxane and prostacyclin.

OBJECTIVE: The study was undertaken to determine the effects of a cyclo-oxygenase II inhibitor on fetoplacental artery production of prostacyclin and thromboxane A(2). STUDY DESIGN: Eight placentas were obtained from normal parturients at delivery and four chorionic plate arteries were dissected from each placenta. Arteries were incubated in media alone, media plus angiotensin II (1x10(-10) mol), media plus rofecoxib (300 ng/mL), or media plus angiotensin II and rofecoxib. Serial samples were assayed for metabolites of thromboxane B(2) and prostacyclin by enzyme-linked immunosorbent assay. Results were compared by analysis of variance, and P<.05 was considered significant. RESULTS: At 24 hours, 6-keto-prostaglandin F(1alpha) levels in the rofecoxib group (1.74+/-1.39 ng/mg tissue, P<.01) and the rofecoxib plus angiotensin II group (2.15+/-1.85 ng/mg tissue, P<.01) were significantly lower than levels in the control group (4.25+/-2.03 ng/mg tissue). Thromboxane B(2) levels were lower in the angiotensin II group (0.65+/-0.33 ng/mg tissue) than the control group (1.22+/-0.70 ng/mg tissue, P<.05). CONCLUSION: Cyclo-oxygenase II inhibition decreases the production of prostacyclin in fetoplacental arteries and alters the normal ratio of thromboxane A(2) to prostacyclin.

Angiotensin II↗