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PubMed1971

Metabolism of benzoic acid by bacteria: 3,5-cyclohexadiene-1,2-diol-1-carboxylic acid is an intermediate in the formation of catechol.

3,5-Cyclohexadiene-1,2-diol-1-carboxylic acid (1,2-dihydro-1,2-dihydroxy-benzoic acid) is converted enzymatically to catechol in cell extracts from Acinetobacter, Alcaligenes, Azotobacter, and three Pseudomonas species. This enzymatic activity is present only in cultures which have been grown in the presence of benzoic acid, and which convert benzoic acid to catechol rather than to protocatechuic acid. The reaction is assayed by the concomitant formation of reduced nicotinamide adenine dinucleotide from nicotinamide adenine dinucleotide. The conversion of [(14)C]benzoic acid to [(14)C]dihydrodihydroxybenzoic acid is demonstrated in cell extracts. A scheme for the conversion of benzoic acid to catechol in bacteria is presented, involving the formation of dihydrodihydroxybenzoic acid from benzoic acid by a dioxygenase which is unstable in cell extracts, followed by the dehydrogenation and decarboxylation of dihydrodihydroxybenzoic acid to catechol by a previously undescribed enzyme. Experiments with anthranilic acid and phthalic acid suggest that dihydrodihydroxybenzoic acid is a metabolite unique to benzoic acid metabolism. Two new methods for assaying benzoic acid dioxygenase are suggested.

Acids↗
PubMed1972

Mutant strains of Escherichia coli K-12 exhibiting enhanced sensitivity to 5-methyltryptophan.

Eighteen mutants (designated MT(s)), isolated in Escherichia coli K-12, showed increased sensitivity to inhibition of growth by 5-methyltryptophan. All mutants were also much more sensitive to 4-methyltryptophan and 7-azatryptophan but exhibited near normal sensitivity to 5-fluorotryptophan and 6-fluorotryptophan. All of the mutations were linked to the trp operon. Their locations within the trp operon were established by deletion mapping. There was good agreement between the map position of an MT(s) mutation and a lowered activity of one of the tryptophan pathway enzymes. Three mutants, one of which contained a mutation that mapped within the trpE gene, were deficient in their ability to use glutamine as an amino donor in the formation of anthranilic acid. Another trpE mutation led to the production of an anthranilate synthetase with an increased sensitivity to feedback inhibition by tryptophan.

Aspartate-Semialdehyde Dehydrogenase↗
PubMed1976

Enhancing effect of allopurinol on the induction of bladder cancer in rats by n-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide.

The effects of allopurinol on the induction of bladder cancer by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), excretion of urinary tryptophan metabolites, hepatic nitroreductase activity, and the acid-soluble thiol content of liver and blood in weanling female Fischer rats were investigated. Four groups of rats were given normal diet or normal diet supplemented with 0.005% allopurinol, 0.188% FANFT, or 0.005% allopurinol-0.188% FANFT. Transitional cell carcinomas appeared in 3 of 30 rats (10%) at 15 weeks and in 7 of 44 rats (16%) at 20 weeks in the FANFT-treated group; the carcinomas appeared in 14 of 35 rats (40%) at 15 weeks and in 27 of 50 rats (54%) at 20 weeks in the FANFT-allopurinol-treated group. Growth rate was not affected by allopurinol and FANFT. Allopurinol alone caused no morphological change in the epithelial cells of the urinary bladder but decreased hepatic cytosol nitroreductase activity. FANFT alone had no effect on hepatic cytosol or microsomal nitroreductase activity but increased hepatic and blood acid-soluble thiol content. FANFT increased the urinary excretion of anthranilic acid glucuronide, kynurenine, acetylkynurenine, and 3-hydroxykynurenine and decreased indican and o-aminohippurate excretion. Allopurinol did not alter the effects of FANFT on the acid-soluble thiol content of liver and blood or the excretion of urinary tryptophan metabolites.

Allopurinol↗
PubMedDate not supplied

[Different effects of kynurenines on rat liver tryptophan pyrrolase activity].

3-Hydroxyanthranilic, quinolinic and nicotinic acids/50 mg/kg, intraperitoneally/increased the content of rat blood plasma 11-hydroxycorticosteroids as well as the activity of liver tryptophane pyrrolase. After administration of anthranili and picolinic acids, elevation in 11-hydroxycorticosteroid content was not followed by an increase in the tryptophane pyrrolase activity. Picolinic acid diminished induction of tryptophane pyrrolase activity by hydroxycortisone and anthranilic acid dicc not affect the induction. Adrenalectomy prevented the increase in tryptophane pyrrolase activity after treatment with nicotinic, quinolinic and 3-hydroxyanthranilic acids. Prolonged augmentation of kynurenines in the organism might be a result of a mediated through corticosteroids increase in the tryptophane pyrrolase activity caused by elevation in the level of 3-hydroxyanthranilic, quinolinic and nicotinic acids.

11-Hydroxycorticosteroids↗
PubMed1984

Suicide inactivation of chymotrypsin by benzoxazinones.

The benzoxazinones 2-ethoxy-4H-3,1- benzoxazin -4-one (1a) and 2-(trifluoromethyl)-4H-3,1- benzoxazin -4-one (1d) inactivate chymotrypsin. The inactivation is stoichiometric and proceeds with rate constants of 7 X 10(5) M-1 min-1 and greater than 4 X 10(6) M-1 min-1, respectively. The inactivated enzyme recovers catalytic activity slowly, k = 2.3 X 10(-3) min-1 and 3.7 X 10(-2) min-1 (pH 7.1). When the enzyme regains catalytic activity, 2-[N-(ethoxycarbonyl)amino]benzoic acid is released from enzyme inactivated with 1a and N-(trifluoroacetyl)anthranilic acid from enzyme inactivated with 1d. The mechanism of inactivation involves attack of the active site serine on the C-4 carbonyl of the inactivator which leads to ring opening and formation of an ortho-substituted benzoylchymotrypsin , which hydrolyzes slowly due to electron releasing ability of the substituents. The rate of hydrolysis of the benzoylchymotrypsin from 1a or 1d is in close agreement with those predicted from the Hammett parameters (sigma, rho) for hydrolysis of their para-substituted analogues [ Caplow , M., & Jencks , W. P. (1962) Biochemistry 1, 883-893]. The inactivation of chymotrypsin by 2-methyl-4H-3,1- benzoxazin -4-one (1b) is an equilibrium process (kinact = 1 X 10(4) M-1 min-1 and Keq = 2 X 10(6) M-1). Formation of a benzoylchymotrypsin is demonstrated by spectral changes and methanol trapping. The benzoylchymotrypsin can also decay by direct hydrolysis to N- acetylanthranilic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Chymotrypsin↗
PubMed1993

Three-dimensional profiles from residue-pair preferences: identification of sequences with beta/alpha-barrel fold.

The three-dimensional profile method expresses the three-dimensional structure of a protein as a table, the profile, which represents the local environment of each residue. The score of an amino acid sequence, aligned with the three-dimensional profile, reflects its compatibility with the profiled structure. In the original implementation, each local environment was characterized by its polarity, the area buried of its side chain, and its secondary structure. Here we describe a modified three-dimensional profile algorithm that characterizes the local environment in terms of the statistical preferences of the profiled residue for neighbors of specific residue types, main-chain conformations, or secondary structure. Combined profiles of the original and the three new types were tested on beta/alpha-barrel protein structures. The method identified the following enzymes of unknown three-dimensional structure as probable beta/alpha-barrels, all of which catalyze reactions in the biosynthesis of aromatic amino acids: anthranilate phosphoribosyltransferase (trpD), glutamine amidotransferase (trpG), and phosphoribosylformimino-5-aminoimidazole carboxamide ribotide isomerase (hisA).

Aldose-Ketose Isomerases↗
PubMed1991

Chinese hamster ovary cell assays for mutation and chromosome damage: data from non-carcinogens.

In vitro genotoxicity tests are employed to screen chemicals for their capability to cause various DNA and chromosomal alterations, and the results are often used to predict their potential for carcinogenicity. However, there is controversy regarding the apparent low specificity of some in vitro genotoxicity assays, which result in a high false positive rate. Since we use and rely upon in vitro assays for risk assessment and prediction of carcinogenicity, this specificity issue is of serious concern to us. Hence, we selected ten compounds deemed non-carcinogens in the literature to test for the induction of gene mutation and chromosomal damage using the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT) mutation assay performed concurrently with a CHO micronucleus assay. The chemical exposures for the two end-points were done simultaneously. The protocol for the two end-points was developed using the carcinogens N-methyl-N'-nitro-N-nitrosoguanidine, 3-methylcholanthrene, cyclophosphamide and 7,12-dimethylbenzanthracene. The non-carcinogens chosen were 4-nitro-o-phenylenediamine, p-phenylenediamine dihydrochloride, 3-nitropropionic acid, dichlorvos, 2-(chloromethyl)pyridine, N-(1-naphthyl)ethylenediamine 2HCl, O-anthranilic acid, 4-nitroanthranilic acid, anilazine and triphenyltin hydroxide. Each of these chemicals had been reported positive in the Ames test and/or the mouse lymphoma TK+/- mutation assay. In addition, eight of them were also reported positive in in vitro assays for chromosome aberrations and/or sister chromatid exchange (SCE). We found four of the ten chemicals negative for gene mutation and micronucleus induction without and with activation in the CHO/HGPRT mutation and CHO micronucleus assays. However, one of these four chemicals may be a potential carcinogen according to other carcinogenicity reviewers. Four other chemicals that induced only micronuclei were negative for gene mutation. Dichlorvos was positive for gene mutation and micronucleus induction without and with activation. This chemical has been shown recently to cause various tumors in rodents. One of the non-carcinogens was positive in the micronucleus test and equivocally positive in the mutation test. These results indicate that the CHO/HGPRT mutation assay may provide more relevant results than the CHO micronucleus assay, the mouse lymphoma mutation assay, or in vitro SCE and chromosome aberration assays when screening chemicals for potential carcinogenicity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment.

The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5 The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2,5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13, 14, 25 and 26, to the anthranilate esters 16, 17, 27 and 28 using N-(trifluoroacetyl)anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18, 19, 29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.

Aconitine↗
PubMed1999

Beta-peptides: twisting and turning.

Oligomers of beta-amino acids (beta-peptides), which are readily available by standard meth ods either in solution or on solid support, adopt a large variety of different secondary structures in solution and in the solid state. beta-Peptides 4, 5 and 10 fold into a helix with 3 residues per turn and 14-membered H-bonded rings (314 helix) that is left-handed for 5 and 10 and right-handed for 2 (due to the reversal of the chirality of the building blocks), as was clearly demonstrated by two-dimensional NMR-spectroscopy. This helix thermally is very stable in methanol solution upon heating. As shown by NMR- and CD-spectroscopy, it is partially populated even at 100 C (Figure 3). Another helix was dis covered for mixed beta-peptide 8 in methanol solution: it is characterized by 12- and 10- membered turns (Figure 4, left) and its central 10-membered turn has been found in the solid state of a geminally disubtituted beta-peptide (Figure 4, right). This central 10-membered turn was used as a scaffold to attach beta-amino acid residues that prefer a linear (non-helical) conformation (beta-peptide 21): a hairpin (pleated sheet-turn-pleated sheet) structure was determined in solution by NMR-spectroscopy (Figure 5). In contrast to this antiparallel pleated-sheet, a parallel pleated sheet was found for a beta-tripeptide in the solid state. For the first time it was possible to observe reversible peptide folding in MD simulations by studying beta-peptides (Figure 6) and to determine folding pathways and intermediates. beta-Peptides are a new class of promising peptidomimetics. They are resistant against the degradation by proteolytic enzymes such as pepsin, elastase, carboxypeptidase A, pro nase or proteasom 20S. A variety of beta-amino acids (27-34) was shown to be non- mutagenic by Ames tests and beta-peptides 47 and 48 reveal large elimination half-lives of 3 h (for 47) and 10 h (for 48) in the serum of rodents (Figure 7). Conjugates of alpha- and beta- peptides are efficient ligands for the HLA*B27 MHC Class I protein, a five fold increase of binding (2.0 microM for 55) compared to a natural peptidic ligand 51 was observed. Furthermore, beta-peptides are able to mimic natural a-peptidic hormones such as somatostatin. The cyclo-beta-tetrapeptide 57 binds to the five human somatostatin receptors in the micromolar range. In addition, several other non-natural oligomers such as beta-peptide nucleic acids (built from 58 and 59), beta-peptoids (60), oligomers of anthranilic acids and beta-sulfonamido peptides are discussed.

Animals↗
PubMed1995

Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase.

Several kynurenine analogues were synthesized and tested as inhibitors of the enzymes kynurenine hydroxylase and/or kynureninase with the aim of identifying new compounds able to inhibit the synthesis of quinolinic acid (an endogenous excitotoxin) and to increase that of kynurenic acid, an endogenous antagonist of ionotropic glutamate receptors. Among these analogues, we selected m-nitrobenzoylalanine (mNBA) as an inhibitor of kynurenine hydroxylase and o-methoxybenzoylalanine (oMBA) as an inhibitor of kynureninase. When administered to rats, mNBA was more potent than oMBA in increasing the content of kynurenine and of kynurenic acid in the brain, blood, liver, and kidney. This confirms that hydroxylation is the main pathway of kynurenine metabolism. Both mNBA and oMBA (50-400 mg/kg i.p.) increased the concentration of kynurenate in hippocampal extracellular spaces (as measured with a microdialysis technique) and, when simultaneously injected, their effects were additive. This biochemical effect was associated with a decrease in locomotor activity in rats and with a protection of audiogenic convulsions in DBA/2 mice. In conclusion, the results of the present experiments indicate the possibility of increasing the neosynthesis of kynurenic acid by inhibiting the enzymes that metabolize kynurenine to 3-hydroxykynurenine or to anthranilic acid. The increased synthesis of kynurenate is associated with behavioral effects such as sedation and protection from seizures, which suggests a functional antagonism of the excitatory amino acid receptors.

Alanine↗
PubMed2003

Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-methyl-3-substituted quinazolin-4-(3H)-ones.

A series of novel 2-methyl-3-substituted quinazolin-4-(3H)-ones have been synthesized by treating (2-methyl-4-oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester with different amines, the starting material dithiocarbamate was synthesized from anthranilic acid. The compounds synthesized were investigated for analgesic, anti-inflammatory and antibacterial activities. All the test compounds exhibited significant activity, the compounds VA2, VA3 and VA4 shown more potent analgesic activity, and the compounds VA3 and VA4 shown more potent anti-inflammatory activity than the reference compound diclofinac sodium.

Administration, Oral↗
PubMed1981

Intestinal absorption of tolfenamic acid at experimental malabsorption states in rats.

Absorption kinetics of 14C-labelled N-(3-chloro-o-tolyl)-anthranilic acid (tolfenamic acid, 14C-TA, Clotam) from the small intestine was studied in intact rats and in rats with malabsorption states provoked by methotrexate, starvation, and triparanol. 14C-TA was administered intravenously and intraduodenally, and the drug concentrations in the blood were followed up radiometrically. A multi-compartmental model was applied for mathematical analysis. Theoretical model parameters were computed, and absorption parameters were then derived from the theoretical ones. The absorption half-life of 14C-TA was 5.3 min in the controls, 10.8 min in the methotrexate-intoxicated, 7.5 min in the fasted, and 5.3 min in the triparanol-intoxicated rats. The absorbed fraction of the intraduodenal 14C-TA dose was 100% in each experimental group as well as in the controls. It is suggested that the slower transfer of 14C-TA through the intestinal barrier in the methotrexate-intoxicated and fasted rats may be caused by the reduction of the absorptive surface.

Animals↗
PubMed1984

Expression of an artificial yeast TRP-gene cluster in yeast and Escherichia coli.

All five tryptophan biosynthetic genes of Saccharomyces cerevisiae were unified on plasmid pME554, which is based on 2 micrometer DNA and pBR322 sequences allowing for autonomous replication in yeast and E. coli. Homologous and heterologous expression of this artificial yeast TRP-gene cluster was studied. Plasmid pME554 allowed for nearly normal growth of a yeast strain bearing auxotrophic mutations in all five TRP-genes. The plasmid-borne genes TRP2 to TRP5 were expressed and regulated normally in the frame of the general control. Gene TRP1, carried on an EcoRI/Bg/II fragment lacking the ARS1 function, was expressed poorly and did not respond to the general control like the chromosomally-borne TRP1 gene. Plasmid pME554 allowed for poor growth of E. coli strain W3110 tna- delta trpEA2 on minimal medium. Marked stimulation was observed, however, when anthranilic acid or indole were added. Accordingly, poor expression of the first Trp-enzyme anthranilate synthase and the last enzyme tryptophan synthase was found, whereas the other three genes were moderately well expressed in E. coli.

Base Sequence↗
PubMed1997

Isolation and characterization of anaerobic indole- and skatole-degrading bacteria from composting animal wastes.

Four species of indole-degrading Clostridium and 3 species of skatole-degrading Clostridium were isolated from piggery or chicken manure composting processes. Since type strains of respective isolates did not degrade these compounds, the degradability of the compounds was a novel characteristic. All isolates were mesophilic. The maximum growth allowance concentrations of these isolates were 300 to 800 mg/l in indole and 100 to 300 mg/l in skatole. All isolates showed better growth and utilization of indolic compounds in nutrient-rich medium than in minimal medium. Skatole-degrading isolates degraded some substituted indoles tested, 3-indoleacetic acid, indole and oxindole, but did not degrade 1-methylindole, 2-methylindole, isatin or anthranilic acid. On the other hand, indole-degrading isolates degraded only oxindole. The growth of Clostridium malenominatum A-3 was inhibited by a low concentration (0.005%) of indole or skatole, even when 200-fold excess glucose was present in the medium. When 0.03% indole or skatole was added to the medium, C. malenominatum A-3 showed a lag phase for about 10 and 70 h, respectively. When 0.01% of these compounds was added to the medium, the uptake of glucose was inhibited. C. malenominatum A-3 degraded these compounds under nutrient-rich and minimal conditions.

Journal Article↗
PubMedDate not supplied

[Syndrome due to acetylsalicylic acid intolerance. What should be prescribed as substitutes for aspirin?].

In the daily practice of allergology, one of our commonest problems concerns the prescription of nonsteroidal anti-inflammatory drugs for our patients who are intolerant of acetylsalicylic acid, whose basic clinical expression of this intolerance is primary bronchial asthma. Our problem is the high frequency with which the syndrome appears after the administration of other analgesics chemically unrelated to acetylsalicylic acid. Most authors accept that derivatives of pyrazolones and indoles, and of phenylisopropionic and anthranilic acids must be avoided. This avoidance is based on collected clinical experience and the currently accepted hypothesis concerning the pathogenesis of the syndrome (pyrazolones, indoles, etc. are inhibitors of the byosynthesis of the E series of prostaglandins, particularly PG synthetase). On the other hand there is no agreement concerning what type of analgesics, anti-inflammatory drugs and antipyretics we should prescribe for these patients. The conclusions of the protocol which we carried out are as follows. Dextropropoxyphene chlorhydrate, diviminol, tilidine chlorhydrate, salicylamide, benzidamine, pentazocine, isonixine, hyoscine bromide and ergotamine tartrate can be prescribed safely for these patients in the usual therapeutic dosage. To the list of prohibitions should be added the derivatives of glaphenine and phenylacetic acid. As regards paracetamol, our opinion is that its use should be restricted to those cases in which the previously listed drugs cannot be substituted for it, and always after administration under medical supervision in a hospital setting.

Analgesics↗
PubMed1995

Synthesis of new 2-([(phenoxy or phenyl)acetyl]amino)benzoic acid derivatives as 3 alpha-hydroxysteroid dehydrogenase inhibitors and potential antiinflammatory agents.

A number of 2-([(phenoxy or phenyl)acetyl]amino)benzoic acid derivatives were prepared in about 50% yield from (phenoxy or phenyl)acetyl chloride and anthranilic acid derivatives. All the compounds were tested as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase, since enzyme inhibition predicts potential antiinflammatory activity in vivo. The most active compounds 3 l, m, s are about 3.5 times more active than acetylsalicylic acid (ASA). Activity is influenced by electronic as well as steric effects.

3-Hydroxysteroid Dehydrogenases↗
PubMed1984

A new strain of Salmonella typhimurium reverted by mitomycin C and N-methyl-N'-nitro-N-nitrosoguanidine--a possible universal tester for mutagenic compounds.

A strain of Salmonella typhimurium, SO1007, which carries the amber mutation trpD28 plus the plasmid pKM101 was reverted very efficiently by two mutagens with different mutagenic specificities and modes of action: mitomycin C (MC) and N-methyl-N'-nitro-N-nitrosoguanidine (NG). By selecting revertants on minimal agar supplemented with anthranilic acid (AA), two distinct phenotypic classes of TrpD28 revertants can be recovered: prototrophs (MM+) and anthranilate utilizers (AA+). Since each phenotypic class is known to be caused by a variety of mutational events, reversion of trpD28 on minimal-anthranilate medium may be useful for detecting mutagenic agents regardless of the types of mutations they may cause. Thus, strains like SO1007 may be useful as 'universal' detectors of mutagenic compounds. In the course of these experiments we also observed that pKM101 does not protect but, on the contrary, sensitizes the host bacteria slightly to the toxic effects of MC.

Methylnitronitrosoguanidine↗
PubMed2006

Prostaglandin E2 release in gastric antral mucosa of guinea-pigs: basal PGE2 release by cyclo-oxygenase 2 and ACh-stimulated PGE2 release by cyclo-oxygenase 1.

Prostaglandin E(2) (PGE(2)), which is generated by two isoforms of cyclo-oxygenase (COX(1) and COX(2)), is a key mediator in gastric mucosal defense. In the present study, antral mucosa of guinea-pigs was incubated with various agonists or antagonists in a medium, the PGE(2) concentration of which was measured using a PGE(2) EIA kit. Prostaglandin E(2) was released from the antral mucosa spontaneously (basal PGE(2) release) and acetylcholine (ACh, 10 microM) enhanced the PGE(2) release (ACh-stimulated PGE(2) release) was mediated via intracellular Ca(2+) concentration ([Ca(2+)](i)). Arachidonic acid enhanced both forms of PGE(2) release, and a phospholipase A(2) inhibitor (amylcinnamoyl anthranilic acid) and COX inhibitors (acetylsalicylic acid and indomethacin) decreased them. 5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazol (SC560, 100 nm, a COX(1)-selective inhibitor) inhibited ACh-stimulated PGE(2) release without any decrease in basal PGE(2) release. N-(2-Cyclohexyloxy-4-nitrophenyl) methanesulphonamide (NS398, 20 microM, a COX(2)-selective inhibitor) decreased basal PGE(2) release without any reduction of ACh-stimulated PGE(2) release. However, ionomycin (a Ca(2+) ionophore) increased PGE(2) release from antral mucosa in the presence of SC560 or NS398, suggesting that COX(1) and COX(2) are regulated by [Ca(2+)](i). These findings indicate that COX(1)-containing cells have ACh receptors but COX(2)-containing cells do not. Moreover, in isolated antral epithelial cells, SC560 decreased basal and ACh-stimulated PGE(2) release, but NS398 did not. In conclusion, in antral mucosa, basal PGE(2) release is mainly maintained by COX(2) of non-epithelial cells, and ACh-stimulated PGE(2) release is maintained by COX(1) of epithelial cells.

Acetylcholine↗