Developmental regulation of endothelial nitric oxide synthase in cerebral vessels of newborn pig by prostaglandin E(2).
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We investigated whether prostaglandins regulate endothelial nitric oxide synthase (eNOS) in the pig cerebral vasculature during the neonatal period. Prostaglandins, eNOS mRNA, eNOS protein, and NO production were higher in cerebral microvessels of newborn (1 day old) than in those of adult (6- to 8-month-old) pigs. The treatment of isolated cerebral microvessels of newborn animals with ibuprofen for 24 h reduced eNOS mRNA and nitrite production to levels in the adult; this effect of ibuprofen was prevented by concurrent treatment with prostaglandin (PG)E(2) analog 16,16-dimethyl-PGE(2), nonselective PGE(2) receptor analog 11-deoxy PGE(1), and prostaglandin EP(3) receptor agonists sulprostone and M&B 28,767 but was not modified by PGI(2) analog carbaprostacyclin, PGD(2), and EP(1) receptor agonist 17-phenyl trinor PGE(2). Correspondingly, 16, 16-dimethyl-PGE(2) and M&B 28,767 increased eNOS mRNA expression of adult microvessels to values in the newborn. Data similar to those with isolated cerebral vessels were obtained through histochemical analysis (NADPH-diaphorase positivity) of brain from newborn animals treated in vivo with ibuprofen in combination or not with sulprostone. Furthermore, substance P-induced NO-mediated cerebral vasorelaxation was decreased to adult values through the treatment of newborn pigs with ibuprofen; this effect was prevented by concomitant treatment with sulprostone. It is concluded that PGE(2) regulates eNOS in newborn pig cerebral microvessels via EP(3) receptors; this may be physiologically required during normal neurovascular development. (+info)
Hepatocytes are a rich source of novel aspirin-triggered 15-epi-lipoxin A(4).
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Novel aspirin (ASA)-triggered 15-epi-lipoxins (ATL) comprise new potent bioactive eicosanoids that may contribute to the therapeutic effect of this drug. ATL biosynthesis is initiated by ASA acetylation of cyclooxygenase (COX)-2 and was originally identified during the interaction of leukocytes with either endothelial or epithelial cells. Here, we examined ATL biosynthesis in rat hepatocytes either alone or in coincubation with nonparenchymal liver cells (NPC) and in liver homogenates from ASA-treated rats. Rat hepatocytes and CC-1 cells, a rat hepatocyte cell line, displayed COX-1 but not COX-2 mRNA expression and predominantly produced thromboxane A(2) (TXA(2)) and 15-hydroxyeicosatetraenoic acid (15-HETE). In these cells, ASA shifted the arachidonic acid metabolism from TXA(2) to 15-HETE in a concentration-dependent manner. In contrast, neither indomethacin, ibuprofen, valeryl salicylate, nor nimesulide was able to trigger 15-HETE biosynthesis. SKF-525A, a cytochrome P-450 inhibitor, significantly reduced the effect of ASA on 15-HETE biosynthesis. Furthermore, phenobarbital, a potent inducer of cytochrome P-450 activity, further increased ASA-induced 15-HETE production. ASA treatment of hepatocyte-NPC coincubations resulted in the generation of significant amounts of ATL. In addition, in vivo experiments demonstrated augmented hepatic levels of 15-epi-lipoxin A(4) in ASA-treated rats. Taken together and considering that ASA is hydrolyzed on its first pass through the portal circulation, these data indicate that, during ASA's consumption, liver tissue generates biologically relevant amounts of ATL by COX-2-independent mechanisms. (+info)
Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen.
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Apoptotic pathways controlled by the Rel/NF-kappaB family of transcription factors may regulate the response of cells to DNA damage. Here, we have examined the NF-kappaB status of several prostate tumor cell lines. In the androgen-independent prostate tumor cells PC-3 and DU-145, the DNA-binding activity of NF-kappaB was constitutively activated and IkappaB-alpha levels were decreased. In contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of NF-kappaB which were upregulated following exposure to cytokines or DNA damage. The activity of the IkappaB-alpha kinase, IKKalpha, which mediates NF-kappaB activation, was also measured. In PC-3 cells, IKKalpha activity was constitutively active, whereas LNCaP cells had minimal IKKalpha activity that was activated by cytokines. The anti-inflammatory agent ibuprofen inhibited the constitutive activation of NF-kappaB and IKKalpha in PC-3 and DU-145 cells, and blocked stimulated activation of NF-kappaB in LNCaP cells. However, ibuprofen did not directly inhibit IkappaB-alpha kinase. The results demonstrate that NF-kappaB is constitutively activated in the hormone-insensitive prostate tumor cell lines PC-3 and DU-145, but not in the hormone responsive LNCaP cell line. The constitutive activation of NF-kappaB in prostate tumor cells may increase expression of anti-apoptotic proteins, thereby decreasing the effectiveness of anti-tumor therapy and contributing to the development of the malignant phenotype. (+info)
A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis.
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OBJECTIVE: Alternative medicine is used extensively by patients with chronic pain due to e.g., osteoarthritis. Only few of these drugs have be tested in a controlled setting and the present study was undertaken to examine the effect of ginger extract, one of the most popular herbal medications. DESIGN: Ginger extract was compared to placebo and Ibuprofen in patients with osteoarthritis of the hip or knee in a controlled, double blind, double dummy, cross-over study with a wash-out period of one week followed by three treatment periods in a randomized sequence, each of three weeks duration. Acetaminophen was used as rescue medication throughout the study. The study was conducted in accordance with Good Clinical Practice (European Guideline for GCP). RESULTS: A ranking of efficacy of the three treatment periods: Ibuprofen>ginger extract>placebo was found for visual analogue scale of pain (Friedman test: 24.65, P< 0.00001) and the Lequesne-index (Friedman test: 20.76, P< 0.00005). In the cross-over study, no significant difference between placebo and ginger extract could be demonstrated (Siegel-Castellan test), while explorative tests of differences in the first treatment period showed a better effect of both Ibuprofen and ginger extract than placebo (Chi-square, P< 0.05). There were no serious adverse events reported during the periods with active medications. CONCLUSION: In the present study a statistically significant effect of ginger extract could only be demonstrated by explorative statistical methods in the first period of treatment before cross-over, while a significant difference was not observed in the study as a whole. (+info)
Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs.
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Several anti-inflammatory drugs have been examined for their ability to cause a time-dependent destruction of the fatty acid oxygenase that produces prostaglandins. All of the time-dependent inhibitors contained carboxylic acid moieties, and in addition all but one of the drugs contained a halogen atom. Structural analogs (of the time-dependent inhibitors) lacking halogen atoms were unable to cause a time-dependent destruction of the enzyme. The time-dependent property of an inhibitor was totally eliminated after methylation of the carboxylate group. Methylation did not, however, alter the ability of the inhibitors to competitively inhibit the oxygenase. Thus, the reversible binding of the agents at the active site was not appreciably dependent upon the free carboxyl group, whereas the subsequent irreversible process was. (+info)
Evidence for paracrine signaling between macrophages and bovine adrenal chromaffin cell Ca(2+) channels.
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The adrenal gland contains resident macrophages, some of which lie adjacent to the catecholamine producing chromaffin cells. Because macrophages release a variety of secretory products, it is possible that paracrine signaling between these two cell types exists. Of particular interest is the potential paracrine modulation of voltage-gated calcium channels (I(Ca)), which are the main calcium influx pathway triggering catecholamine release from chromaffin cells. We report that prostaglandin E(2) (PGE(2)), one of the main signals produced by macrophages, inhibited I(Ca) in cultured bovine adrenal chromaffin cells. The inhibition is rapid, robust, and voltage dependent; the activation kinetics are slowed and inhibition is largely reversed by a large depolarizing prepulse, suggesting that the inhibition is mediated by a direct G-protein betagamma subunit interaction with the calcium channels. About half of the response to PGE(2) was sensitive to pertussis toxin (PTX) incubation, suggesting both PTX-sensitive and -insensitive G proteins were involved. We show that activation of macrophages by endotoxin rapidly (within minutes) releases a signal that inhibits I(Ca) in chromaffin cells. The inhibition is voltage dependent and partially PTX sensitive. PGE(2) is not responsible for this inhibition as blocking cyclooxygenase with ibuprofen did not prevent the production of the inhibitory signal by the macrophages. Nor did blocking the lipoxygenase pathway with nordihydroguaiaretic acid alter production of the inhibitory signal. Our results suggest that macrophages may modulate I(Ca) and catecholamine secretion by releasing PGE(2) and other chemical signal(s). (+info)
Regulation of endothelial nitric oxide synthase by PGD(2) in the developing choroid.
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We investigated if prostaglandins might regulate the increased choroidal endothelial (e) nitric oxide synthase (NOS) expression in the perinate. Prostaglandins, eNOS mRNA, immunoreactive protein and activity, and nitrite [stable metabolite of nitric oxide (NO)] production were markedly higher in newborn (1 day old) than juvenile (6-8 wk old) pig choroid. Treatment of isolated newborn choroids with the prostaglandin synthase inhibitor ibuprofen for 24 h reduced eNOS mRNA and nitrite production to values in juveniles. This effect was equally observed with the PGD(2) receptor (DP) blocker BW A868C and was prevented by cotreatment with PGD(2) but not other prostaglandins; similar observations were made on NOS activity in vivo. PGD(2) also increased eNOS expression on choroids of juveniles, and this effect was blocked by BW A868C. The manifestation of this upregulation of eNOS by PGD(2) on the control of choroidal vasomotor response was tested by using NO-dependent vasorelaxants, ACh, bradykinin (Bk), and substance P (SP). ACh-, Bk-, and SP-elicited choroidal vasorelaxation was greater in saline-treated newborn than juvenile pigs. Ibuprofen (24 h) decreased ACh-, Bk-, and SP-evoked vasorelaxation in newborns, whereas PGD(2) increased that in juveniles and prevented the ibuprofen-induced attenuated relaxation in newborns; infusion of N(omega)-monomethyl-L-arginine in choroids of those animals treated with PGD(2) reversed the augmented vasorelaxation to ACh, Bk, and SP. Finally, PGD(2)-induced upregulation of NOS in the perinate was also reflected by curtailed choroidal blood flow autoregulatory response to increased perfusion pressure. In conclusion, PGD(2) exhibits a major role in upregulating eNOS expression and activity in the choroid, which in turn results in greater NO-mediated vasorelaxation; a new mechanism for eNOS regulation via DP is hereby disclosed. The relationship between PGD(2) and eNOS in the developing subject provides an explanation for the interactive role of these two factors in the absent choroidal blood flow autoregulation in the perinate. (+info)
Pharmacoepidemiology of non-steroidal anti-inflammatory drug use in Nottingham general practices.
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AIM: To investigate the pharmacoepidemiology of NSAID usage in Nottingham general practices. DESIGN: Questionnaire sent to 1137 consecutive recipients of an NSAID prescription from 21 doctors in six general practices with computerized records. Patient responses were subsequently linked to data held on the practice records. SETTING: General practices in and around Nottingham, selected to reflect local variations in number of partners, list size, geographical location, deprivation, prescribing burden and prescribing rate. SUBJECTS: Unselected patients receiving NSAIDs prescribed for all indications. MAIN OUTCOME MEASURES: Indication for treatment, differences in prescribing to different age groups, compliance and overall scheme drug exposure, drug effectiveness and tolerability, possible drug-related adverse events, patients' overall satisfaction with treatment and estimated costs of care. RESULTS: NSAIDs were used for a wide range of conditions and only a small number of patients had rheumatoid arthritis. The main drugs used were ibuprofen, diclofenac and naproxen. Patients making short-term use of NSAIDs had low compliance if they experienced adverse drug effects, whilst conversely in long-term users, those with high compliance reported more adverse drug effects. Calculated compliance did not vary with age although older patients (over 65 years) claimed in their questionnaires to be more compliant than younger patients. Half the patients reported good or complete symptom relief. Half of those questions (and two thirds of those with good or complete symptom relief) rated their NSAID as the best treatment they had received for their current condition. The frequency of gastrointestinal adverse events was higher in the young and the old, which correlated with the use of anti-ulcer drugs, and increased with the total number of medications used. CONCLUSIONS: NSAIDs are used for a wide-range of conditions. They give symptom relief to, and are perceived as effective by, most patients taking them. (+info)