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PubMed1986

Meclofenamate sodium is an inhibitor of both the 5-lipoxygenase and cyclooxygenase pathways of the arachidonic acid cascade in vitro.

Meclofenamate sodium was compared to other nonsteroidal antiinflammatory drugs in terms of its potency to inhibit the formation of 5-HETE and LTB4 in human leukocytes and the formation of prostaglandin E2 in bovine seminal vesicles as measures of its ability to inhibit the 5-lipoxygenase and cyclooxygenase pathways of the arachidonic acid cascade. Meclofenamate sodium was about 2-4 times less potent than BW-755C in inhibiting 5-lipoxygenase enzyme activity and three times more potent than benoxaprofen, while naproxen, ibuprofen, and indomethacin showed IC50 greater than 100 microM. Meclofenamate sodium and indomethacin were the most potent inhibitors of the formation of PGE2 in bovine seminal vesicles followed by ibuprofen, naproxen, and benoxaprofen in this order. Meclofenamate sodium, like BW-755C, can be considered a dual inhibitor of 5-lipoxygenase and cyclooxygenase pathways of arachidonic acid cascade. This finding may explain in part the antiinflammatory activity of meclofenamate sodium.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1983

Production of prostaglandins E2 and F2 alpha in the freshwater mussel Ligumia subrostrata: relation to sodium transport.

Pharmacological experiments indicate that prostaglandins (PGs) have a role in the control of sodium regulation in freshwater mussels and the mechanism may be linked to cyclic AMP and serotonin. To test this hypothesis we used radioimmunoassay to investigate the ability of freshwater mussels to synthesize PGs. The levels of precursor fatty acids were determined in a gas-liquid chromatograph. Arachidonic acid (precursor to the diene PGs) was the major fatty acid component of total lipids in the gill and accounted for 14% of the total. In addition, gill homogenates synthesize PG-like material from [3H]arachidonic acid. Material corresponding to PGE2 and PGF2 alpha were identified on thin-layer radiochromatograms. These data indicate that gills (the primary site of Na transport) can produce PGs. The presence of PGs in freshwater mussels was verified by radioimmunoassay of blood. Both PGE2 and PGF2 alpha were identified using highly specific antisera. The concentrations of both PGs was significantly reduced when the mussels were injected with inhibitors of phospholipase A2 or cyclooxygenase before sampling blood. Stimulation of Na transport by serotonin and cyclic AMP results in a depression of blood PGE2 with no effect on circulating PGF2 alpha. PGE2 levels are inversely correlated with net Na flux. These data indicate endogenous PGE2 negatively modulated Na transport and PGE2 levels are regulated by a serotonin-cyclic AMP mediated system.

Animals↗
PubMed1988

Arachidonate-dependent oxygen consumption in Dictyostelium discoideum.

A central feature of the processes of aggregation and differentiation in the cellular slime mould Dictyostelium discoideum is the periodic excitatory cycle. Originally thought to involve primarily fluctuations in cyclic AMP levels, this excitatory cycle has since been shown to involve changes in several other second messengers including cyclic GMP, calcium and inositol trisphosphate. Previous work from this laboratory using specific inhibitors strongly suggested a role for eicosanoids in this stimulus-response process. Production of eicosanoids from fatty acid precursors is an oxygen-consuming process. In this paper, we report on oxygen consumption measurements in intact D. discoideum cells and in cell extracts. We demonstrate the existence of an azide-insensitive component of oxygen consumption which can be stimulated by the addition of arachidonate and other polyunsaturated fatty acids, and at least partially inhibited by meclofenamate and eicosatetraynoic acid, both of which block eicosanoid biosynthesis in higher organisms. These observations provide further evidence for the existence of an eicosanoid-metabolizing system in D. discoideum.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1989

In vitro reactivity of dog cavernous carotid artery to stretch and adrenergic stimulation.

The reactivity of the dog cavernous carotid artery to stretch, field electrical stimulation, and norepinephrine was studied using arterial segments under isometric conditions. Light microscopy revealed that this artery is of muscular type and its external surface is covered by venous endothelium, and fluorescence microscopy showed a dense adrenergic innervation. On stretch, arteries exhibited an immediate, transient contraction (phasic response) and a late, maintained contraction (tonic response) that were unaffected by tetrodotoxin (10(-6) M) or endothelium removal but were reduced by the inhibitors of cyclooxygenase indomethacin (10(-6) M), acetylsalicylic acid (3 x 10(-5) M), or meclofenamate (10(-5) M). Electrical stimulation (0.5-4 Hz) contracted the arteries in a frequency-dependent manner, and the response was reduced by tetrodotoxin, phentolamine, (10(-6) M), or the inhibitors of cyclooxygenase used but was unaffected by endothelium removal. Norepinephrine (10(-9)-3 x 10(-4) M) caused dose-dependent contraction that was blocked by phentolamine and by the inhibitors of cyclooxygenase but was not modified by endothelium removal. The results indicate that the dog cavernous carotid artery develops myogenic tone on stretch and contracts on adrenergic stimulation. They also suggest that in these responses prostaglandins but not the endothelium are involved. Therefore, the cavernous carotid artery, because of its location and reactivity, could be of relevance in regulating blood flow or pressure within the cerebral circulation when arterial pressure or adrenergic activity increases.

Acetylcholine↗
PubMed1993

Importance of prostanoids in calcium chelator-induced airway constriction.

To elucidate the mechanism of calcium chelator-induced airway constriction, we examined the relationship between prostanoids and histamine in bronchoalveolar lavage (BAL) fluid and the magnitude of airway constriction in peripheral airways of anesthetized Basenji-Greyhound dogs. A wedged bronchoscope technique was used to measure collateral system resistance (Rcs) before and after aerosol challenges. Sublobar segments were challenged either with acetylcholine or with Na2EDTA in the presence or absence of meclofenamate sodium (3 mg/kg iv) or methylprednisolone (2 mg.kg-1.day-1). After measurements of Rcs, BAL was performed, and the fluid was analyzed for prostanoids with the use of gas chromatography-mass spectrometry. Sublobar segments challenged with Na2EDTA showed increased concentrations of prostaglandin (PG) D2 but no increases in PGE2, PGF2 alpha, 9 alpha,11 beta-PGF2, 6-keto-PGF1 alpha, thromboxane B2, or histamine. There was a strong relationship (r = 0.84, P = 0.005) between changes in Rcs after Na2EDTA and concentrations of PGD2 in BAL fluid. Acetylcholine, which increased Rcs to a similar degree as Na2EDTA did, produced no significant increase in prostanoid concentrations. Changes in Rcs after Na2EDTA and concentrations of PGD2 were reduced in the presence of meclofenamate or methylprednisolone. These data support the idea that the mechanism of calcium chelator-induced bronchoconstriction involves the release of bronchoconstricting prostanoids.

Acetylcholine↗
PubMed1998

Fenamates protect neurons against ischemic and excitotoxic injury in chick embryo retina.

Three fenamates (flufenamate, meclofenamate and mefenamate) were examined for their protective effect on neurons under ischemic (glucose/oxygen deprivation) or excitotoxic conditions, using the isolated retina of chick embryo as a model. Retinal damage was evaluated by histology and lactate dehydrogenase assay. Whole-cell recording was used to examine the direct effect of the fenamates on glutamate receptor-mediated currents. The fenamates protected the retina against the ischemic or excitotoxic insult. Part of the neuroprotection by the fenamates derived from inhibition of N-methyl-D-aspartate receptor-mediated currents. However, kainate receptor-mediated currents were not blocked by the fenamates, which nonetheless reduced kainate receptor-mediated retinal damage. Our results raise the possibility that fenamates may serve as lead structures in the development of novel therapeutic agents against brain ischemia.

Animals↗
PubMed1990

Inhibition of human periodontal prostaglandin E2 synthesis with selected agents.

Considerable evidence has demonstrated the importance of PGE2 synthesis in the pathogenesis of periodontal disease. Although various cyclooxygenase inhibitors have been known to block periodontal PGE2 synthesis and prevent disease progression in animal models, there are few reports comparing relative efficacies of various inhibitors of arachidonic acid (ARA) metabolism. We have developed a sensitive in vitro assay to measure PGE2 synthesis in periodontal tissues. The apparent IC50 values (i.e. the concentration of drug which causes 50% inhibition of maximum PGE2 synthesis) have been determined for a series of arachidonic acid analogues as well as competitive and non-competitive cyclooxygenase inhibitors. Periodontal tissue homogenates were incubated in the presence of 3H-arachidonic acid for 45 min at 37 degrees C. Inhibitors were tested at 10(-10)-10(-4) M and at zero concentration to measure conversion of 3H-arachidonate to 3H-PGE2. Log or half log dilutions of inhibitors were tested in triplicate for each assay. Radiolabeled PGE2 was extracted from homogenates, purified by reverse phase chromatography and quantitated by double antibody capture. RIA was performed on each homogenate to determine the amount of endogenous unlabeled PGE2 present in the sample to correct for antibody capture recovery. The apparent IC50 values were determined for each drug by averaging two or more replicate assays. Specific total enzymatic activity of periodontal tissue homogenates was typically 5-11 pg PGE2/min/mg tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1975

Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs.

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.

Anti-Inflammatory Agents↗
PubMed1993

Elevated glucose and angiotensin II increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells.

The lipoxygenase (LO) pathway of arachidonate metabolism has been suggested to play a key role in atherosclerosis and in mediating several actions of angiotensin II (AII). However, the relationship between LO activation and factors linked to accelerated diabetic vascular disease such as hyperglycemia and AII is not known. We have investigated the effect of high glucose (HG; 25 mM) and AII on LO activity as well as LO protein and mRNA expression in porcine aortic vascular smooth muscle cells (PVSMCs). We observed that cells cultured in HG had significantly higher levels of the cell-associated LO products 12- and 15-hydroxyeicosatetraenoic acids (HETEs). AII added to cells grown in HG specifically further increased only cell-associated 12-HETE levels. Using immunoblot analysis and reverse transcriptase PCRs, we demonstrated the presence in PVSMCs of porcine leukocyte-type 12-LO protein and mRNA, respectively. Furthermore, the levels of both were markedly upregulated by AII as well as by HG. These studies suggest that enhanced 12-LO activity and expression are mechanisms for accelerated vascular disease produced by HG and AII in diabetes mellitus.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1986

Inhibition of trans-dihydrodiol oxidation by the non-steroidal anti-inflammatory drugs.

The homogeneous dihydrodiol dehydrogenase of rat liver cytosol (EC 1.3.1.20) reduces the mutagenicity of benzo[a]pyrene in the Ames test, suggesting that the enzyme may detoxify the trans-dihydrodiol proximate carcinogens formed from this compound. This report directly demonstrates for the first time that the purified dehydrogenase catalyzes the NADP-dependent oxidation of the potent proximate carcinogen [1,3-3H](+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene at physiological pH. An initial velocity of 1.8 nmol [3H]trans-dihydrodiol oxidized/min/mg protein was observed at a substrate concentration of 20 microM. This potential detoxification reaction was potently inhibited by the nonsteroidal anti-inflammatory drug indomethacin, yielding an IC50 value of 10 microM. At higher drug concentrations (30 microM), the inhibition persisted for many hours. In an extension of this work, benzenedihydrodiol (trans-1,2-dihydroxy-3,5-cyclohexadiene) and naphthalenedihydrodiol (trans-1,2-dihydroxy-1,2-dihydronaphthalene) were synthesized as models of the scarce proximate carcinogen trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and examined as substrates. The Km for benzenedihydrodiol was 1.74 mM and the Vmax was 530 nmol substrate oxidized/min/mg protein, while the Km for naphthalenedihydrodiol was 10.71 mM and the Vmax was 268 nmol oxidized/min/mg protein; the former compound was oxidized to catechol. Eight different non-steroidal anti-inflammatory drugs were found to inhibit the oxidation of these model trans-dihydrodiols, yielding IC50 values comparable to or lower than peak plasma concentrations observed in man. These results suggest that therapeutically relevant concentrations of the non-steroidal anti-inflammatory drugs may inhibit the oxidation of trans-dihydrodiol proximate carcinogens by this route.

3-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Effects of anti-inflammatory agents on hydrochloric acid-induced pulmonary injury.

To determine the effects of anti-inflammatory agents on hydrochloric acid lung injury, the heart and lungs were harvested from rats, placed in a lung chamber, constant flow perfused with whole blood, and ventilated. The following experiments were conducted: observation alone; intratracheal injection of normal saline; intratracheal hydrochloric acid; and intravenous meclofenamate or indomethacin before intratracheal hydrochloric acid. Wet-to-dry lung weights were measured. Peak airway pressures increased immediately (p < .001 vs. baseline; ANOVA) in all intratracheal groups, hydrochloric acid producing even greater (p < .05) increases than saline-effects unaltered by meclofenamate or indomethacin. The increased (p < .001 vs. baseline) 2-h pulmonary artery pressures in hydrochloric acid-treated groups were unaltered by meclofenamate or indomethacin. All hydrochloric acid-treated groups demonstrated increases (p < .05) in weight that were unchanged by meclofenamate or indomethacin. These data suggest that the beneficial effects of these medications described elsewhere, using a variety of in vivo lung injury experimental models, may be attributed to their experimental design, or to contributions from organs/systems outside the pulmonary circuit.

Acute Disease↗
PubMed1996

Impairment of vascular function is associated with an age-related increase of lipid peroxidation in rats.

We tested the hypothesis that an increase in endogenous lipid peroxidation over time is associated with an impairment of endothelium-dependent vascular function in resistance-sized mesenteric arteries that is due in part to alterations of arachidonate metabolism. Susceptibility to red blood cell hemolysis and sera levels of malondialdehyde were increased (P < 0.05) from 20 wk (n = 12) to 40 wk (n = 12) in female Sprague-Dawley rats. Arteries were studied in a myograph by examining the endothelial modification of phenylephrine vasoconstriction and the relaxation responses of the mesenteric arteries to methacholine. We observed the following. 1) An increase in sensitivity to alpha 1-adrenergic stimulation occurred between 20 and 40 wk of age. Cyclooxygenase inhibition decreased the sensitivity to phenylephrine only in the arteries from the 40-wk-old rats, indicating that a cyclooxygenase-dependent vasoconstrictor was modifying the phenylephrine response. 2) Nitric oxide synthase inhibition caused a greater increase in phenylephrine sensitivity in the arteries from the 20-wk-old rats than those from the 40-wk-old rats, indicating that nitric oxide modification of phenylephrine sensitivity decreased with age. 3) Endothelium-independent relaxations were not affected between 20 and 40 wk of age. 4) At 40 wk, the sensitivity to the methacholine-mediated relaxation response decreased without impairing the maximal relaxation response. This reduced sensitivity was removed with cyclooxygenase inhibition or thromboxane A2/prostaglandin H2 (PGH2) receptor blockade. 5) Aortas from the 40-wk-old rats had an increased expression of PGH synthase. Collectively, these observations indicate that, in the female rat, an increase in lipid peroxidation over time is associated with changes in endothelium-dependent vascular function that were due in part to a cyclooxygenase-dependent vasoconstrictor.

Aging↗