synthesis thromboxane - gut · conducted to determine factors influencing (a) the synthesis of...

Gut, 1986, 27, 1484-1492

Synthesis of prostaglandin E2, thromboxane B2and prostaglandin catabolism in gastritis andgastric ulcerC J HAWKEY(WITH THE TECHNICAL ASSISTANCE OF N K BHASKAR AND B FILIPOWICZ)

From the Department of Therapeutics, University Hospital, Nottingham

SUMMARY Because endogenous prostaglandins may protect the gastric mucosa a study wasconducted to determine factors influencing (a) the synthesis of immunoreactive prostaglandin(iPG) E2 and thromboxane (iTx) B2 as measured by radioimmunoassay and (b) prostaglandincatabolism measured radiometrically, in human gastric mucosa. Gastric mucosa was obtained atendoscopy. Synthesis of iPE2 and iTxB2 was inhibited in vitro by indomethacin; iTxB2 synthesiswas also selectively inhibited by the thromboxane synthesis inhibitor dazmegrel. Prostaglandincatabolism was inhibited by carbenoxolone. Multivariate analysis showed that synthesis of iPGE2from endogenous precursor during homogenisation was decreased in patients on non-steroidalanti-inflammatory drugs. Mucosal inflammation was associated with significantly increasedsynthesis of iPGE2 and decreased prostaglandin catabolism. There were no differences betweenthe mucosa of patients with or without gastric ulcers, nor between the ulcer rim and mucosa 5 cmaway. Age, sex, smoking history, and ingestion of antisecretory drugs appeared to exert noinfluence. In this study gastritis was the major influence on prostaglandin synthesis. It seems

unlikely that prostaglandin deficiency is a strong predisposing factor for gastric ulceration.

Reports suggesting gastric mucosal protection byendogenous prostaglandin synthesis'-3 raise thepossibility that this process might be defective inpatients who develop gastric ulcers. Previous evi-dence on this point has been conflicting. Somestudies have found reduced prostaglandin synthesisin gastric ulcer patients,4 even in the presence ofgastritis: this would be surprising because otherinflammatory lesions lead to enhanced prostaglan-din synthesis. Another study reported increasedprostaglandin synthesis in patients with gastriculcers6 and attributed this to the associated gastritis:however, even where this occurs it remains possiblethat prostaglandin synthesis could be deficient inrelation to the prevailing levels of mucosal in-flammation.

Factors other than reduced prostaglandin synth-esis might render the mucosa liable to ulcerate.These could include an absolute or relative enhance-

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ment of thromboxane synthesis as thromboxanesynthesis is associated with gastric ulceration in ratsand inhibitors of thromboxane synthesis appear tobe protective.7 Alternatively reduced levels ofprotective prostaglandins might result from in-creased prostaglandin catabolism.'2I3

In this study synthesis of immunoreactive prosta-glandin (iPG)E, and of thromboxane (iTx)B,, alndprostaglandin catabolism in humatn gastric mucosahave been investigated with reference both tohistological appearances and to the presence orabsence of gastric ulcerattion. The relationship ofage, sex or smoking or ingestion of non-steroidalanti-inflammatory drugs (NSAIDS) or antisecretorydrugs to these parameters has also been investigatedin view of the known influence of these factors onthe incidence or natural history of gastric ulceration.

Methods

PATI ENTSThe following radiolabelled compounds were used:(H3)PGE,, 160 Ci/mmol (Amersham International);

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(H3) TxB1, 139 3 Ci/mmol (New England Nuclear)and (9 H3)PGF1. 13 7 Ci/mmol (Amersham Interna-tional). The following compounds were gifts: in-domethaicin (Merck Sharp & Dohme). dazmegrel(Pfizer UK). carbenoxolone (Biorex Laboratories).TxB, antiserum wtas kindlv donated by Dr LawrenceLevine. PGE, antiserum wias bought from theInstitut Pasteur. Other chemicals were obtainedfrom standard lAboratory suppliers.

Patients undergoing upper gastrointestinal endo-scopy with an Olympus T endoscope were studied.Where there was a possibility that mucosa might betaken for research patients were asked to givewritten informed consent before the endoscopy. Thestudy was approved by the South NottinghamEthical Committee.

In studies used to develop and validate theincubation conditions and radioimmunoassalys andto assess reproducibility with repeated study. bothnormail subjects aind paitients with a vairiety ofgastroduodenal conditions were studied. During themnain study 27 patients with gastric ulcers and 43control patients were studied. As gastritis was one ofthe factors which the study wats designed to investi-gate. endoscopic or histological evidence of in-flarmmation was not an exclusion criterion. In allother respects. the control patients had normalendoscopic findings. The ch aracteristics of thepatients studied are detailed in Table 1.

HIS 1(IOGYFour to five mucosail biopsy specimens were taIkenfrom the lesser curve between 45 and 50 cm from theincisor teeth and used immediately. A small piecefrom two of the specimens, or a separate biopsyspecimen from the sarme irea wats exatmined histolo-gically (without knowledge of the biochemical re-sults) and graded as uninflamed (normal or only

Table I (Characteristics of tile 1i)(lit.e.s Istdied

Control GU p)atielIS

Total 43 27Mcn 29 13Stilokcrs 16 17Antisecrctory dtirgs 9 17NSAIDS 5 4Agc <3(0 ysears 7

3(-50 II-50-65 9 1165-75 11 1475+ 4

Pa'aticnts on rcgular NSAID's. last dosc in cach case approximiatcly12 hours bcforc cindoscopsy Individual druLgS aIS follows:-indomcthacin: flivc, ispirin: tsAo. naproxen: onc. flurhuprotcn:onc.

slight increase in inflarmmatory cell infiltrate) orinflamed (moderate or matrked increatse in in-flammatory cell infiltraite) using staindard histologicalcriteria of inflammation. No attempt was maide todifferentiate between inflammnation caused malinlyby neutrophils and inflarmmation caused mainly bylymphocytes. As mucosal atrophy and Imlucosailinflammation were frequently associated no attemptwas made to assess them independently.

HOMOGENATES ANI) INCUBATIONSThe rest of the biopsy specimens were homogenisedimmediately on ice in Tris HCI t)()5M. pH 7-4 (20mg wet weight/ml finatl proportions) for 15 secondsusing an Ultraturax homogenizer.

SYNTHESIS FROM ENDOGENOUS STORES(ENDOGENOUS iPGE2ANI) iTxB,)Ten milligram aliquots in 0 5 ml (final proportions)of the homogenaite were extracted immediately intochloroform,'1 for the determination of prostanoidssynthesised from endogenous stores (henceforthdesignated Endogenous iPGE, or iTxB ).

INHIBITOR EXPERIMENTSSome samples were pre-incubated in Tris HCIcontaining either indomethacin 50 [tg/ml (4x 10 4M)for 15 minutes before being homogenised in freshTris HCI also containing indomethacin 50 Rg/ml(4x10-4 M). These samples were extracted in theusual way and results compared with those obtainedfrom biopsies from the same patient but not exposedto indomethacin.

SYNTHESIS AFTER INCUBATION WITH ARACHIDONICACID (TOTAL iPGE2 SYNTHESIS)Other aliquots (10 mg, 0 5 ml, final proportions)were incubated with arachidonic acid 2 utg for 30minutes at 37°C in a rocking water bath beforeextraction into chloroform.'5 Because this proce-dure results in synthesis of prostanoids from bothendogenous and exogenous arachidonic acid it isdesignated Total iPGE2 synthesis.

INHIBITOR EXPERIMENTSIn some experiments aliquots of homogenates wereincubated with or without indomethacin 1 [ig/ml(2*8x10-6M) or dazmegrel 0-3 [tg/ml (10-6M). Theeffect of the inhibitor was calculated after allowancefor synthesis during homogenisation.

RADIOIMMUNOASSAYSAfter extraction into chloroform, samples wereresuspended in phosphate buffered saline (pH 7-40-15 M), and stored at -50°C for radioimmunoas-say, usually within one month (maximum three

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months). iTxBI3 was measured by radioimmunoassayusing anti-serum kindly donated by Dr LawrenceLevine. For thromboxane assays standard TxB,,TxBI anti-serum and H13] TxB2 tracer (Amersham)were dissolved and samples were diluted in Trissaline pH 7-4, 0-15 M with 1% gelatin. iPGE2 wasmeasured by radioimmunoassay as previouslydescribed. 16 17

CATABOLISMAliquots of homogenate (10 mg 0 5 ml, final propor-tions) were also incubated with (90-H3)PGF2,(1 mg, 0-1 iCi) and NAD 1 mm for five minutes at37°C. They were extracted into chloroform at pH3 5 and re-suspended in 75 Rl; chloroform:ethanol(1:1). PGF,(L and its metabolites were separated bythin layer chromatography using Watman LK6Dsilica gel chromatography plates and ethyl acetate:acetone:acetic acid (90:10: 1) as solvent. Regionscorresponding to authentic PGF,(,, 15 keto PGF,,,13 14 dihydro PGF2, and 13 14 dihydro 15 ketoPGF2, were scraped and added direct to LKBOptiphase scintillant for quantitation by liquidscintillation counting. Radioactivity cochromato-graphing with metabolites was expressed as a percent of total radioactivity scraped. A similar valuederived using boiled mucosa from the same patientwas then deducted to obtain values for the percen-tage of enzymatic catabolism in samples.

INHIBITOR EXPERIMENTSIn some experiments, aliquots of the homogenatewere preincubated on ice for 15 minutes withcarbenoxolone 57 sg/ml (10-4 M) or 5-7 [sg/ml10-5 M) and then incubated with (9ji-H3)PGF2(,(1 [tg, 25 nCi) and NAD 1 mm for 15 minutes at370C.

STATISTICAI. MLTHOI)SThe catabolism data approximated to a normaldistribution but all synthesis data were transformedlogarithmically to obtain a normal distribution foranalysis. The influence of gastritis, gastric ulcera-tion. age, sex, smoking, drug ingestion, and studynumber (to allow for any changes in experimentaltechnique with time) upon prostaglandin synthesisand catabolism were investigated by multivariateanalysis (Statistical Package for Social SciencesProgramme). Paired data were evaluated using thepaired t test.

Results

VAl II)ITY Of RADIOIMMUNOASSAYS(i) iPGE,In these experiments assay of samples at two-fold

dilutions gave similar results (value at higher dilu-tion 99+3%/,, SEM, of value at lower dilution, n=6).Authentic PGE, added to samples before extractionwas assayed as 103±4°/O (n=48) of that added.Prostaglandin E, re-assayed in samples after one tothree months of storage was 105±9'S (n=101) ofinitial value. The PGE, antiserum showed selectivereactivity with material cochromatographing withauthentic PGE,.

(ii) iTxB2Under the assay conditions used, the cross reactivityof the TxB2 antiserum with other prostanoids (basedon concentrations required to produce 50% dis-placement of (H3) TxB2) was as follows: PGD2:1-2%; PGFia: 0(12%; PGE2: 0 1%; PGF2a: 0-01%;arachidonic acid, PGA2, 6 keto PGFI(, and 13 14dihydro 15 keto PGE2: all <0-001%. Assay ofsamples at two dilutions gave similar results (valueat higher dilution=105+5% of value at lowerdilution, n=15). Authentic TxB2 added to samplesbefore or after extraction was assayed as 90+9%(n=20) of that added. TxB2 re-assayed after one tothree months of storage was 109+1% (n=53) ofinitial value. TxB2 anti-serum showed selectivereactivity with material cochromatographing withauthentic TxB2.

QUAILITY CONTROLPreliminary experiments showed that iPGE2 andiTxB, (measured by radioimmunoassay) were re-covered to a similar extent (69+1% for PGE2 and69±2"/o for TxB,) (n=3 each). In subsequentexperiments (H3)PGE, was used to measure recov-ery: mean recoveries were 72%. Three externalstandards of PGE, or of TxB, were included in eachradioimmunoassay and two samples previouslyassayed satisfactorily were re-assayed to ensureaccuracy and consistency from one assay to another.

HOMOGENATESEFFECTS OF INHIBITORS IN VITRO(a) Immediate extraction (Endogenous iPGE2 andTxB,)Synthesis of iPGE2 was inhibited by 60±8% (n=8)if homogenisation was carried out in the presence ofindomethacin, 50 sg/ml (1 4x 10-4 M). Under theseconditions synthesis of iTxB2 was reduced by68±6% (n=8).

(b) Incubated synthesisSynthesis of iPGE2 was inhibited by 72±9% and ofiTxB2 by 63±15% (n=4) by indomethacin 1 sg/ml(2.8x 10-6 M). The thromboxane synthesis inhibitordazmegrel 0-3 Fg/ml (10-6 M) inhibited iTxB2synthesis by 44+21%; synthesis of iPGE2 was243±69% control (n=4).

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(c) CatabolismCarbenoxolone inhibited prostaglandin catabolismby 29±9% at 10-5 M (n=8) and by 79±5% at10-4 M) (n=6).

REPRODUCIBILITY

Eighteen patients were studied on two occasionsafter receiving in the intervening period, misopros-tol (n=7), trimoprostil (n=4), placebo (n=4), cime-tidine (n=2) and ranitidine (n= 1). Two way analysisof variance showed that patients differed significantlyfrom each other but that there was no significantchange after the period of treatment. Based on theresidual variance, the coefficients of variation forrepeated study were: for endogenous iPGE2: 14%;for total iPGE2: 10%; for iTxB2: 17% (all logarith-mically transformed data) and for prostaglandincatabolism (untransformed data): 33%.

INFI UENCE OF PATIENT CHARACTERISTICS ON

SYNTHESIS AND CATABOI ISM

Table 2 shows all factors having a statisticallysignificant or near significant influence on thedependent variables studied. Where patients were

studied more than once the first data only were

Table 2 Factors influencing the synthesis and catabolismof prostanoids in human gastric mucosa

)ependentvari(blec 1i Influence IR F p

Ln(Endo- 64 NSAIDS -0-31 8X3( <()0()1gcnous Inliammation () 2X X 39 <()0()1PGE,) C1u -0-15 3-73* <() 1

Ln(Total 60 Inflamiaiation 0(37 9X81 <((I1PGE,) Study numiibcr (032 7-015 <()0()5

Ln(TXB,) 45 Studs uLmtibicr 0(42 8X99 <()0()1GlU -()028 3-85, <01;

Catabolism 7(0 StuLy nunibcr 032 8X68 <01Inflaimmi,ation -0-23 5-1(0 <()-()5

Ln= natural logarithmR=simplc corrclation cociticicnt F=variancc iatio"Critical F vislucs - 40)) (p<) ()5), 2X80 (p<() 1())-,-Critical F salLICs - 4-08 (p<()-()5). 2-85 (p<()-I()The Tablc only shows thosc varirlbcs whcrc a p vlaluc Icss than ()0 1was obtaincd.

Hanvkev,

used. Inflammation wits aI miajor influence and was

associated with increased synthesis of iPGE2 (bothendogenous and total) as well as reduced prosta-glandin catabolism (Fig. 1). Patients takinig non-

steroidal anti-inflammrinatory drugs showed reducedsynthesis of prostanoids (Fig. 1): this was statisti-cally significant for endogenous iPGE,. The studynumber was a significant influence on prostagliandincatabolism, Total iPGE. and iTxB.: values of alllthree increatsed gradually as the study progressed.Finally there were trends towards lower levels ofiPGE, and of iTxB. in patients with gastric ulceria-tion but these did not reach conventional levels ofsignificance. No other factor showed statisticallysignificant influence.

UlCER RIM VERSUS INTAC[r MUCOSA

In lX patients mucosa wals obtained from the rim ofthe gastric ulcer: ulcerated slough and fibrous tissuein the base were avoided. Synthesis of iPGE., iTxB,and prostaglandin catabolism in the ulcer rim was

compared with that from mucosa on the lesser curve

at least 5 cm away. As seen in Figure 2 there is littledifference between the ulcer rim and the intactmucosa.

PAIRFI) DATA, GASTRIC ULICER VERSUS

NON-GASTRIC Ul.CER PATIENTS

Twelve pairs of patients could be identified, matchedfor levels of inflammation, drug intake, sex, age (towithin seven years) and study date (to within threemonths), differing only with regard to the presenceor absence of gastric ulceration. There were no

significant differences in the synthesis of iPGE,,iTxB, or of prostaglandin catabolism (Fig. 3).

Discussion

The main conclusions from these data are thatiPGE, synthesis as meiasured in the study is in-

creased and that prostaglandin catiabolism is re-

duced in the presence of gastritis. After allowing forthe influence of coexisting inflammiation, however,there were no significant differences between gastricmucosa from patients with or without gastric ulcera-tion.

Radioimmunoassays were used as the bases ofmeasurement for synthesis. In these studies as with

Fig. 1 Svntihesis anid catabolism of prostatloids in gastric mnuco.sa: effect of gastrilis and ga.stric ulceration. (a) iPGE,sPthesised from enidogeioul sub.strate (Endogenoli.s iP(E,) in pgmlng wet weight. (h) Total iP(GE, (after incubation- williexogenous arachidonic acid) in pgl ing wet ueight. (c) iTvB, (.synilhesisedfromergdogenous .sore.s) iip mg et ucight.(d) Catabolism of (913)H- PGF,(,:t(Y conversion to metabolite.s calculated Jas described ini text. 0 repre.sent fpatietsA takingnon-steroidal anti-in flainmatory drugs. * - all otlher patients.. s/iou'meanis. Stipp)le(l area,s shlow SEM's.


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others using radioimmunoassay it is possible thatcrossreacting substances were at least in part mea-

sured. This is acknowledged by use of the termsimmunoreactive PGE2 or TxB2 although it seems

unlikely that another s-ibstance would cross reactwith the antiserum, cochromograph with the prosta-

noid and that its synthesis would be inhibited in an

appropriate way by indomethacin or dazmegrel. Therather modest reduction (60-70%) in immuno-reactive prostanoids synthesised during homogenis-ation achieved by high concentration of indomethacincould be taken as evidence that substances other

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than cyclo-oxygenase products were measured.Greater inhibition was seen, however, with lowerconcentration of indomethacin in the incubatedhomogenates and other explanations for the resultsobtained during homogenisation are more likely:there may have been incomplete diffusion of in-domethacin and consequently only partial cyclo-oxygenase inhibition so that some synthesis occurredduring homogenisation. The present results are alsoconsistent with earlier data and the suggestionaccompanying them that in gastric mucosa theremay in fact be a small resting content of prostanoids'8though methodological difficulties make it impossibleto resolve this point with certainty.

Prostaglandin catabolism was measured radiomet-rically. Prostaglandin F,,, was used as substratebecause of its resistance to non-enzymatic catabol-ism. The assay is of enzyme activity in a definedsystem and should not be taken to imply that PGF),,is normailly the main prostaglandin catabolised bythis pathway. Inhibition of prostaglandin catabolismby carbenoxolone has been reported before. In thepresent study different methodology has been usedto confirm that carbenoxolone inhibits prostaglan-din catabolism with a potency similar to thatpreviously reported. 9

The enhianced synthesis of iPGE, with gastritispresumably reflects the infiltration of the mucosa byinflammatory cells: human neutrophils and mac-rophages both have the capacity to synthesisePGE,.-") These differences between inflamed anduninflamed mucosa are similar to those shown bySchlegel et al." Doubt has been expressed as to thevalidity of these earlier data as the amounts of PGE,synthesised appeared to be very high. In the presentstudy the quantities measured were much lower butthe pattern of results was the same. The reduction inprostaglandin catabolism in inflamed tissue has notbeen shown before. Two main explanations arepossible. One is that a primary defect in prostaglan-din catabolism leads to increased mucosal levels ofpro-inflammatory prostaglandins and makes themucosa more liable to become inflamed. Analternative explanation is that the reduced prosta-glandin catabolism is a consequence rather than acause of the inflammation: gastric mucosa has anexceptionally high capacity for prostaglandincatabolism'12 13 which might fall because of themucosal atrophy which accompanies the inflamma-tion in gastritis.Whatever the mechanism, increased synthesis and

reduced catabolism of prostaglandins would bothlead to increased tissue levels in gastritis. As withulcerative colitis, the significance of increased pros-taglandin synthesis in gastritis must be viewed in thecontext of the known properties of prostaglandins.2'

In both situations, it is difficult to ascribe a centralrole to prostaglandins because they do not haveproperties which make them likely to cause recruit-ment of inflammatory cells or to lead to mucosalatrophy. Vasodilator prostaglandins may, however,give rise to mucosal redness sometimes seen inassociation with acute superficial gastritis. Themediators responsible for the recruitment ofinflammatory cells in gastritis however remainunidentified. Obvious candidates which requireinvestigation are leukotriene B4 and other relatedchemotactic lipoxygenase products.

Although there were large differences betweenpatients the data show reasonable within patientconsistency on repeated study, despite interveningtreatment with a variety of therapeutic agents. Thepurpose of the reproducibility study was to validatethe methodology rather than investigate the effectsof individual drugs and the numbers are too small toexclude the possibility that some of the treatmentsinfluenced subsequent prostanoid synthesis. Anti-secretory drug treatment, however, was not asignificant influence on any of the variable investi-gated in the main study in contrast with the earliersuggestion that cimetidine enhances gastric mucosalprostaglandin synthesis. 22The present results are different from those

obtained by Wright et a both in showing enhancedsynthesis with gastritis and in failing to find signifi-cant differences in patients with gastric ulceration.Trends toward lower levels of endogenous iPGE,and of iTxB, in gastric ulcer patients do not reachstatistical significance and no difference was seen inthe comparison of matched pairs of patients.Moreover, there were no local changes in PGE, orTxB. synthesis or prostaglandin catabolism in theulcer rim. Thus in this study gastric ulceration seemsat best to be a much weaker influence thansuggested by Wright et al who reported reducedlevels of PGE, in patients with gastric ulcers evenwhen the mucosa was inflamed.4 There was noevidence of an imbalance between PGE2 and TxB2.The reasons for the differences betweeen the

present data and those of Schlegel et al on the onehand and those reported by Wright et a14 on theother are not clear. The use of homogenates mightbe insensitive to subtle changes in cyclooxygenaseactivity and it remains possible that changes inprostanoid synthesis could occur in vivo because ofphospholipase activation, the influence of neuralstimulation or changes in endogenous synthesis.Specific evidence for such changes in gastric ulcerpatients is lacking, however, and these possibilitiescould not account for the differences between thethree studies as all used homogenates. The controlsin the present study were 43 patients in whom no

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Humanl gastric prostfanoids 1491

pathology was found whereas Wright et al usedseven normal volunteers. One point that emergedfrom the use of the patient study number as a qualitycontrol measure was that there was a tendency forall parameters measured to rise slightly in valueduring the course of the study (presumably becauseof subtle changes in methodology). Because thegastric ulcer patients and their controls were studiedconcurrently these changes do not influence thecomparison between them. Comparable data arenot provided in the other studies.One stimulus for this study was the observation

that the incidence of gastric and duodenal ulcerationis static or rising in older women in the UnitedKingdom but falling in other groups.23 24 Although abalanced group of patients with a wide age distribu-tion was studied there was no evidence that theparameters measured were influenced by age, sex,or smoking. Patients on NSAID's, however, showedreduced prostaglandin synthesis even though theywere studied more than 12 hours after their lastdose. Comparable differences between patients noton NSAID's and controls were not seen suggestingthat reduced prostaglandin dependent processes areless important in this group than in patients takingNSAID's. Wright et al regarded the reduction insynthesis of PGE, which they observed with gastriculcer to be a secondary phenomenon. The datareported in the present paiper give even fewergrounds for believing that a primary deficiency ofprostaglandin synthesis accounts for the develop-ment of gastric ulceration in patients not onNSAID's and thus cast some doubt on the clinicalrelevance of using prostaglandins for mucosal pro-tection of these patients.

This work was supported by a project grant from theMedical Research Council.

References

I Konturek SJi Pialstucki I. Brzozowski T. et til. Roic oflocally generaited prostaglandins in adaptivc gastriccytoprotection. Dig Dis Sci 1982; 27: 967-71.

2 Robcrt A, Nezamis JE. Liancaster C. Davis JP, FicidSO, Hanchar AJ. Mild irritiants present gastric necrosisthrough 'adiaptive cytoprotection' mediated by prostia-glandins. Am J Physiol 1983; 245: G113-G21.

3 Hawkey CJ, Rampton DS. Prostaiglandins iand thegastrointestinal mucosa; are they importaint in itsfunction, disease or treatment'? Gastroentterology 1985;89: 1162-88.

4 Wright JP, Young GO. Klaft LJ, Wcerss LA, Price SK,Marks IN. Gatstric mucosal prostaiglandin E levels inpatients with gastric ulcer disease and carcinoma.Gastroenterology 1982; 82: 263-7.

5 Konturek SJ. Actions of nonsteroid ainti-inflatmmatorycompounds on gastric mucosal integrity and prostaglan-din formaition in heialthy subjects and peptic ulcerpatients. Adi, IlflJamnl(ltioln Res 1984; 6: 29-37.

6 Schlegel W, Wenk K. Dollinger HC, Raptis S. Concen-trations of prostaglandin A-, E- and F-like substancesin gastric mucosat of normal subjects and of patientswith various gaistric diseaises. Clin Sci Mol Medl 1977;52: 255-8.

7 Whittle BJR. Kauffman GL, Moncada S. Vasoconstric-tion with thromboxane A, induces ulceration of thegatstric mucosa. Nature 1981; 292: 472-4.

8 Konturek SJ, Brzozowski T, Piastucki I, Radecki T,Dembinska-Kiec A. Role of prostaglandin aind throm-boxane biosynthesis in gastric necrosis produced bytaurocholate and ethanol. Dig Dis Sci 1983; 28: 154-60.

9 Whittle BJR. Cellulair mediiators in gastric damage:actions of thromboxiane A, and its inhibitors. In: AllenA, Flemstrom G, Giarner A, Silen W. Turnlberg LA,eds. Mechanismns otf sinicosail protectioni in t11e pplergastroinitestinal tract. Raven Press: New York, 1984:295-302.

1() Hawkey CJ, Kemp R. Filipowicz B, Bh3askar NK, WaltRW. Gaistric mucosail protection with dazmegrel, aninhibitor of gastric mucosal thromboxane synthesis.(Gastroeniterology 1985; 88: 1415.

11 Bhaskair NK, Filipowicz B. Hawkey CJ. Inhibition ofhumain gastric mucosal thromboxane synthesis byWHR 2348A. Br J Pharmacol 1985: 85: 268p.

12 Spenney JG. Barton JC. 15 hydroxyprostaglandindehydrogenase aind 13 reductiasc content of gastrointes-tinal organs of rabbits and rats. Prostaglandinis 1981; 21suppl: 15-24.

13 Peskar BM, Seyberth HW, Peskiar BA. Synthesis indmetabolism of endogenous prostaglandins by humiangastric mucosa. In: Sommelsson B. Ramwell PW,Paoletti R. eds. Advances in prostaglandin and1l tlhroitn-boxanie resealrch, vol 8, New York: Riaven Press, 1980:1511-4.

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