Cytoprotection by Prostaglandins in Rats
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GASTROENTEROLOGY 77:433-443,1979 ALIMENTARY TRACT Cytoprotection by Prostaglandins in Rats Prevention of Gastric Necrosis Produced by Alcohol, HCl, NaOH, Hypertonic NaCl, and Thermal Injury ANDRk ROBERT, JAMES E. NEZAMIS, CLEO LANCASTER, and ALEXANDER J. HANCHAR Department of Experimental Biology, The Upjohn Company, Kalamazoo, Michigan Oral administration to fasted rats of either absolute ethanol, 0.6 N hydrochloric acid, 0.2 N sodium hy- droxide, 25% sodium chloride, or boiling water pro- duced extensive necrosis of the gastric mucosa. Pre- treatment with several prostaglandins of the A, E, or F type, either orally or subcutaneously, prevented such necrosis, and the effect was dose-dependent. This property of prostaglandins is called “cyto- protection.” The protective effect against oral ad- ministration of absolute ethanol was already maxi- mal 1 min after PGE, given orally, and 15-30 min after PGE, given subcutaneously. Cytoprotection by prostaglandins is unrelated to the inhibition of gas- tric acid secretion since, (a) it is maximal at doses that have no effect on gastric secretion, and (b) anti- secretory compounds (cimetidine, methscopolamine bromide) and antacids are not cytoprotective. AI- though the mechanism of gastric cytoprotection is unknown, prostaglandins appear to increase the re- sistance of gastric mucosal cells to the necrotizing effect of strong irritants. These results suggest that certain prostaglandins, by a mechanism other than the inhibition of gastric acid secretion, maintain the cellular integrity of the gastric mucosa, and might be beneficial in the treatment of a variety of diseases in which gastric mucosal injury is present. Several prostaglandins (PG) have been shown to in- hibit gastric secretion in animals’-” and humans.4-6 Received October 13,1978. Accepted February 27.1979. Address requests for reprints to: Andre Robert, M.D., Ph.D, De- partment of Experimental Biology, The Upjohn Company, Kala- mazoo, Michigan 49001. The authors thank Dr. Eugene D. Jacobson, University of Cin- cinnati College of Medicine, for his valuable suggestions, and for proposing the term “cytoprotection” after examining our data. 0 1979 by the American Gastroenterological Association. 0016-5085/79/090433-11/$02.00 They also prevent ulcer formation in animals’,“,’ and accelerate ulcer healing in humans.*.’ It was usually assumed that the antiulcer effect was due to the in- hibition of gastric acid secretion. We now present evidence that PG can prevent the formation of gas- tric lesions, even mucosal necrosis, produced in rats by a variety of necrotizing agents, without reducing gastric acid secretion. This property of prostaglan- dins is called “cytoprotection.” An abstract has been published earlier.“’ Methods In all the studies reported here, female rats (Up- john rats derived from the Sprague-Dawley strain) of a body weight of 205-215 g were used. Food, but not water, was removed in the morning. At ~:OO pm, water was also withheld, and the animals were placed in individual cy- lindrical stainless-steel cages with flat bottoms and with perforations to allow ventilation. These cages limited their movements and thus prevented the ingestion of hair and feces. This procedure, as described earlier,’ did not appear to be stressful; actually, the animals were often observed to be asleep in such cages. On the following morning, vari- ous necrotizing agents (listed below) were given orally, and the animals were killed 1 hr later. Their stomachs were dissected out, opened along the greater curvature, and the mucosa was examined by an observer, who was unaware of the treatment given, with a 2~ binocular mag- nifier for the presence of necrotic lesions which were counted. The prostaglandins were administered at multiple dose levels. The results were plotted on semilog paper. The or- dinate shows either the average number of lesions per stomach as such or as a percent of the control values. The abscissa shows the doses on a log scale. The ED,,, is the dose of PG reducing the average number of lesions per stomach by half in comparison with control values, as de- termined by graphic interpolation on a plot of the dose on a log scale. The number of animals per group is indicated in the tables and legends for figures. In all studies, the Stu-
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Transcript of Cytoprotection by Prostaglandins in Rats
GASTROENTEROLOGY77:433-443,1979 ALIMENTARYTRACT CytoprotectionbyProstaglandinsinRats PreventionofGastricNecrosisProducedby Alcohol,HCl,NaOH,HypertonicNaCl,and ThermalInjury ANDRkROBERT,JAMESE.NEZAMIS,CLEOLANCASTER, andALEXANDERJ.HANCHAR DepartmentofExperimentalBiology,TheUpjohnCompany,Kalamazoo,Michigan Oraladministrationtofastedratsofeitherabsolute ethanol,0.6 Nhydrochloricacid,0.2 Nsodiumhy- droxide,25% sodiumchloride,orboilingwaterpro- ducedextensivenecrosisofthegastricmucosa.Pre- treatmentwithseveralprostaglandinsoftheA,E,or Ftype,eitherorallyorsubcutaneously,prevented suchnecrosis,andtheeffectwasdose-dependent. Thispropertyofprostaglandinsiscalledcyto- protection.Theprotectiveeffectagainstoralad- ministrationofabsoluteethanolwasalreadymaxi- mal1minafterPGE,givenorally,and15-30min afterPGE,givensubcutaneously.Cytoprotectionby prostaglandinsisunrelatedtotheinhibitionofgas- tricacidsecretionsince,(a)itismaximalatdoses thathavenoeffectongastricsecretion,and(b)anti- secretorycompounds(cimetidine,methscopolamine bromide)andantacidsarenotcytoprotective.AI- thoughthemechanismofgastriccytoprotectionis unknown,prostaglandinsappeartoincreasethere- sistanceofgastricmucosalcellstothenecrotizing effectofstrongirritants.Theseresultssuggestthat certainprostaglandins,byamechanismotherthan theinhibitionofgastricacidsecretion,maintainthe cellularintegrityofthegastricmucosa,andmightbe beneficialinthetreatmentofavarietyofdiseasesin whichgastricmucosalinjuryispresent. Severalprostaglandins(PG)havebeenshowntoin- hibitgastricsecretioninanimals-andhumans.4-6 ReceivedOctober13,1978.AcceptedFebruary27.1979. Addressrequestsforreprintsto:AndreRobert,M.D.,Ph.D,De- partmentofExperimentalBiology,TheUpjohnCompany,Kala- mazoo,Michigan49001. TheauthorsthankDr.EugeneD.Jacobson,UniversityofCin- cinnatiCollegeofMedicine,forhisvaluablesuggestions,andfor proposingthetermcytoprotectionafterexaminingourdata. 01979bytheAmericanGastroenterologicalAssociation. 0016-5085/79/090433-11/$02.00 Theyalsopreventulcerformationinanimals,,and accelerateulcerhealinginhumans.*.Itwasusually assumedthattheantiulcereffectwasduetothein- hibitionofgastricacidsecretion.Wenowpresent evidencethatPGcanpreventtheformationofgas- triclesions,evenmucosalnecrosis,producedinrats byavarietyofnecrotizingagents,withoutreducing gastricacidsecretion.Thispropertyofprostaglan- dinsiscalledcytoprotection.Anabstracthasbeen publishedearlier. Methods Inallthestudiesreportedhere,femalerats(Up- johnratsderivedfromtheSprague-Dawleystrain)ofa bodyweightof205-215gwereused.Food,butnotwater, wasremovedinthemorning.At~:OO pm,waterwasalso withheld,andtheanimalswereplacedinindividualcy- lindricalstainless-steelcageswithflatbottomsandwith perforationstoallowventilation.Thesecageslimitedtheir movementsandthuspreventedtheingestionofhairand feces.Thisprocedure,asdescribedearlier,didnotappear tobestressful;actually,theanimalswereoftenobserved tobeasleepinsuchcages.Onthefollowingmorning,vari- ousnecrotizingagents(listedbelow)weregivenorally, andtheanimalswerekilled1 hrlater.Theirstomachs weredissectedout,openedalongthegreatercurvature, andthemucosawasexaminedbyanobserver,whowas unawareofthetreatmentgiven,witha2~binocularmag- nifierforthepresenceofnecroticlesionswhichwere counted. Theprostaglandinswereadministeredatmultipledose levels.Theresultswereplottedonsemilogpaper.Theor- dinateshowseithertheaveragenumberoflesionsper stomachassuchorasapercentofthecontrolvalues.The abscissashowsthedosesonalogscale.TheED,,,isthe doseofPGreducingtheaveragenumberoflesionsper stomachbyhalfincomparisonwithcontrolvalues,asde- terminedbygraphicinterpolationonaplotofthedoseon alogscale.Thenumberofanimalspergroupisindicated inthetablesandlegendsforfigures.Inallstudies,theStu- 434ROBERTETAL. GASTROENTEROLOGYVol. 77. No. 3 dentst-testwasusedtodeterminestatisticalsignificance. GastricLesionsProducedbyVarious NecrotizingAgents Oneofthefollowingagentswasgivenorallyina volumeof1ml:absoluteethanol,0.6NHCl,0.2NNaOH, 25%NaCl,andboilingwater.Inthecaseofboilingwater, theanimalswerefirstanesthetizedwithsodiummethoxi- tal(BrevitalSodium,EliLillyandCo.),12mgin0.6mlin- traperitoneally,topreventpain.Anesthesiawasfoundnot tointerferewiththeproductionofa gastricburn. EffectofPGonGastricLesionsProducedby SeveralNecrotizingAgents SeveralPGwereadministeredatvariousdoses,ei- therorallyorsubcutaneously,30minbeforeadministra- tionofeachofthenecrotizingagentsmentionedabove. ThesePGwere:PGE,,16,16-dimethylPGE,,15(S)-15- methylPGF,,,15(R)-15-methylPGF,,,and16,18dimethyl PGA,.ThePGwerefirstdilutedwithafewdropsof95% ethanolandthenmadeuptoavolumeof1 mlwitheither water(oral)orsaline(subcutaneous).Theanimalswere killed1 hrafterreceivingthenecrotizingagents. ComparisonofOralandSubcutaneous Routes BothPGE,and16,16-dimethylPGE,weregivenat variousdoselevels,eitherorallyorsubcutaneously,30 minbeforeoraladministrationof1 mlabsoluteethanol. Theanimalswerekilled1 hrafterreceivingethanol. OnsetofActionandDurationofAction PGE,(500pg/kg)wasgivenorallyorsubcutane- ouslyatvarioustimesupto5hrbeforeoraladministra- tionof1 mlofabsoluteethanol.Controlanimalsreceived 1mlofvehicleatthesametimeintervalsbeforeadminis- trationofethanol.Theanimalswerekilled1 hrafterre- ceivingethanol. EffectoftheVolumeofDiluent Tofindoutwhether,whenthePGweregiven orally,thecriticalfactorwasthetotalamountofPGorthe concentrationofPG,threedosesofPGE,wereadminis- teredinvariousvolumesofdiluent,namely0.5,1.0,and 2.0ml.ThedosesofPGE,were10,25,and100pg/kg.Ab- soluteethanol(1ml)wasgiven30minlater,andtheani- malswerekilled1 hrafterreceivingethanol. 16,26-DimethylPGE,andAbsoluteEthanol, bothGivenafterPylorusLigation Inafirststudy,boththenecrotizingagent(abso- luteethanol)andthecytoprotectiveagent(16,16-dimethyl PGE,)wereadministeredorallyafterligationofthepy- lorus,toseewhetherthePGcouldprotectbydirectcon- tactwiththegastricmucosa.Thepyloruswasfirstligated underetheranesthesia.16,16-DimethylPGE,wasthen givenorally2minlaterat1.5and5.0pg/kg.Tenminutes afterthePG,1mlofabsoluteethanolwasgivenorally. Theanimalswerekilled1 hrlater. Inanotherstudy,16,16-dimethylPGE,wasinjectedsub- cutaneouslyimmediatelyafterpylorusligation,at1.5and 5.0pg/kg.Thirtyminuteslater,inordertoallowenough timeforabsorptionofthePGfromtheinjectionsite,1 ml ofabsoluteethanolwasadministeredorally.Theanimals werekilled1 hrafterreceivingethanol. EffectofCytoprotectivePGonGastric Secretion TofindoutwhethercytoprotectivePGaffected gastricacidsecretion,severalPGweretestedintwodif- ferentpreparations:(a)Shayrats(pylorusligated),and(b) intact,unoperatedrats.TheadvantageoftheShayratis thatitpermitscollectionofallgastricjuicethataccumu- latesduringagiventimeinterval.Theadvantageofthein- tact,unoperatedratisthatthesecretionobtainedisinflu- encedonlybythetreatmentgiven,inthiscaseaPG,andis notalteredbypylorusligation,aprocedureknownto stimulategastricacidsecretion. ShayRats.Aftera24hrfast,theanimalsreceived orallyeither1mlofwater(controls)orofPG.ThePGs usedandtheirdosesareshowninTable2.Onehourlater, thepyloruswasligatedunderetheranesthesia.Theani- malswerekilled4hrafterpylorusligation,andgastric juicewascollected.Thevolumewasmeasured,andthe acidcontentwastitratedwithNaOH0.1NtopH7witha glasselectrode,usinganautomatictitrator(Copenhagen Radiometer).Theresultswereexpressedinmeq/liter (concentration)andmeq/4hr(output).ThedosesofPG werechosentobefrom40-500timesgreaterthanthecyto- protectivedosesinordertofindoutwhethertheseprosta- glandinsaffectedgastricsecretionevenwhengivenat dosesmuchinexcessofthecytoprotectivedose. Intact,UnoperatedRats.Theanimalswerefasted for24hrasaboveandthengiven16,16-dimethylPGE,,1 pg/kgorallyin1 ml.Thisdoseis20timeshigherthanthe cytoprotectiveED,,.Groupsof12ratswerekilledatthe followingintervalsaftertreatment:1,5,15,and30min. Controlsreceived1mlofwaterorallyandwerekilledat thesametimeintervals.Atautopsy,theesophagusandthe pyloruswereclamped,andgastricjuicewascollectedinto atesttube.Sincetherewastoolittlesecretionfordirect titration,thevolumewasfirstmeasured,andthen1mlof waterwasaddedtothetesttube.Theacidityofthedi- lutedjuicewasdeterminedbytitrating0.5mlwith0.1N NaOH.Theamountofacidinthestomachwascalculated asfollows: Vol.ofjuiceVol.ofjuicepeq/ literof beforedilutionxafterdilutionxdilutedjuice~2 Vol.ofjuiceafterdilutionminus1 mlX 1000 Acidin = stomach in peq September1979 GASTRICCYTOPROTECTIONBYPROSTAGLANDINS435 Example:0.4 x1.4X 6200 X 2 = 17.36peq/stomach [1.4- 1.01x 1000 Thisstudywasdonetofindoutwhethergastricacidse- cretionwasdecreasedatanytimeduringthe30minafter treatmentwithaPG,since,inotherexperimentsreported here,necrotizingagentswereadministered30 minaftera PG. EffectofAntisecretoryDrugsandofAntacids onGastricNecrosisProducedbyAbsolute Ethanol Twogastricantisecretorydrugs,cimetidine(ahis- tamineH,receptorantagonist)50mg/kgintraperitoneally, andmethscopolaminebromideorPamine@(ananti- cholinergic,UpjohnCo.)10mg/kgsubcutaneously,were giveneither30 min(cimetidine)or1hr(methscopolamine bromide)beforeoraladministrationof1mlofabsolute ethanol.Controlanimalsreceivedsaline.Twoantacids, sodiumbicarbonate0.15MandaTrisbufferatpH7(0.15 M),weregivenorallyin2mltoothergroups,1 minbefore oraladministrationof1mlofabsoluteethanol.Control animalsreceived2mlofwater.Theanimalswerekilled1 hrafterreceivingabsoluteethanol. Results GastricLesionsProducedbyVarious NecrotizingAgents Eachofthesefiveagentsproducedseveregas- tricdamagevisiblefromtheoutsideofthestomach asthickblackorredlines.Afteropeningthestom- ach,lesionswerefoundinthemucosaandconsisted ofelongatedbands,l-10mmlongbyl-3mmwide, usuallyparalleltothelongaxisofthestomach(Fig- ure1).Theircolorvariedwiththeagent:yellowor red(ethanol),red(25%NaCl,boilingwater),black (0.6NHCl,0.2NNaOH).Usually,15-20lesions couldbecounted.Theywerelocatedmostlyinthe corpus(theportionofthestomachsecretingacid andpepsin);theantrumwaslessaffected.Nogross lesiondevelopedintheforestomach(thenon- secretingpartcoveredwithasquamousepithelium). Histologically,thelesionsconsistedofnecrosis usuallyextendingdownthroughabouttwo-thirdsof themucosa(involvingthesurfaceepithelium,there- gionofmucusneckcells,andofparietalcells);occa- sionally,thenecrosisinvolvedthefullmucosal thickness.Necroticpatcheswerealsopresentinthe Figure1.Gastriclesionsproducedbyfivenecrotizingagents.Allagentsweregivenorallyin1ml,andtheanimalswerekilled1 hrlater. Stomachswereopenedalongthegreatercurvature.A.Control.B.Absoluteethanol.C.0.6NHCl.D.0.2NNaOH.E.25%NaCl. F.Boilingwater.Inallcases:extensivenecroticlesionsofthecorpus.Theantrumisalmostintactgrossly,althoughlesions werepresenthistologically.Theforestomach(upperwhiteportion)isintact. 436ROBERTETAL. GASTROENTEROLOGYVol.77,No.3 Figure2.Gastriccytoprotectionofprostaglandinsagainstabsoluteethanol.Onemlofabsoluteethanolwasgivenorallyandtheani- malswerekilled1hrlater.A.Controlvehiclegivenorally36minbeforeethanol.Multipleandseverenecroticlesionsofthe corpuscausedbyabsoluteethanol.InB,CandD,a prostaglandinwasadministered30minbeforeethanol.B.PGE,500pg/kg subcutaneously.C.PGE,150pg/kgorally.D.16,16DimethylPGA,50pgg/kgorally.Thesethreeprostaglandinspreventedthe formationofgastriclesionsbyabsoluteethanol. antralmucosa.Mucuscellsofthecorpuswerede- pletedofgranules(asshownbyPASstaining), sometimeseveninareasthatwerenotnecrotic. Largeglobsofmucuswerepftenfoundinthelumen andwereparticularlyabundantafteradministration ofboilingwater;sometimesthesemassesofmucus werestillattachedtothemucosaandcontainedmu- cosalcells,eitherisolatedorasdetachedfragments ofthemucosa.Themuscularismucosaewasintact. Thesubmucosaofthecorpus,theantrum,andthe forestomachwasmarkedlythickenedbyedema,but wasnotnecrotic.Theedematoussubmucosadidnot containpolymorphonuclearleucocytes1hrafterad- ministrationofthenecrotizingagents.Inotherstud- iesinwhichtheanimalswerekilled24hrafterthe necrotizingagents,thesubmucosawasstill markedlyedematousand,inaddition,wasinfil- tratedwithpolymorphonuclearleucocytes.Atthat time(24hr),mostofthemucosahadbecomene- crotic.Inanimalspretreatedwithacytoprotective PGandinwhichnogrosslesionswerevisible,the histologyofthestomachshowedanormalmucosa (nonecrosis,intactmucosalcells)andanormalsub- mucosa(noedema,noinfiltrationwithpolymorpho- nuclearleucocytes).Thesehistologicalfindingswill bereportedindetailelsewhere. September1979 GASTRICCYTOPROTECTIONBYPROSTAGLANDINS 437 Figure3.Gastriccytoprotectionbyprostaglandinsagainstboilingwater.RatswhosestomachsareshowninB,C,andDreceived1mlof boilingwaterorallyandwerekilled1 hrlater.A.Untreatedcontrol.B.Controlvehiclegivenorally30minbeforeboilingwa- ter.Massivenecrosisofthecorpuscausedbyboilingwater.CandD.X,16-DimethylPGE,5pg/kgeitherorally(C)orsubcuta- neously(D),30minbeforeboilingwater.Completeprotection. EffectofPGonGastricNecrosisProducedbypg/ kg,whereasothersrequiredupto500pg/ kgtoin- SeveralAgents hibitthelesions.Figure4showsthecytoprotective effectoffivePG,givenorally,againstgastricmu- ThePGsusedpreventedtheformationofgas-cosalnecrosisproducedbyabsoluteethanol.The triclesions,regardlessofthenecrotizingagentusedprotectionwasdose-dependent.ThemostpotentPG (Figures2and3).TheonlydifferenceamongthePGswas16,16-dimethylPGE,.Figure5showstheeffect wastheirpotency:somewereactiveatlessthan1ofl6,16-dimethylPGE,,givenorally,ongastricmu- 438ROBERTETAL. GASTROENTEROLOGYVol.77,No.3 GASTRI CLESI ONS 100 5101525501 150( 500 0. 025 pgl hgORALLY 100300 Figure4.Gastriccytoprotectionbyfiveprostaglandinsagainst absoluteethanol.Theprostaglandinswereadminis- teredorally30minbeforegiving1mlofabsoluteeth- anolorally.Animalswerekilled1hrafterethanol.The verticalaxisshowstheaveragenumberoflesionsper stomachineachgroup,expressedaspercentofcon- trols(controlanimalsreceivedethanolbutnoprosta- glandin).Eachprostaglandinreducedthenumberofle- sionsperstomachinadose-dependentmanner.The mostpotentprostaglandinwas16,16-dimethylPGE,. Tenratsperpoint. cosallesionsproducedbyfivedifferentagents.Inall cases,thecytoprotectiveeffectwasdose-dependent. ThecytoprotectiveED,,of16,16-dimethylPGE, rangedfrom0.03to0.15pg/kg,dependingonthe necrotizingagent. ComparisonofOralandSubcutaneous Routes. PGE,and16,16-dimethylPGE,wereabout3-4 timesmorecytoprotectivewhengivenorallythan whengivensubcutaneously(Figure6).Theircyto- protectiveED,,wereasfollows:PGE,,25pg/kg orallyand100pg/kgsubcutaneously;16,16-dimethyl PGE,,0.05pg/kgorallyand0.15pg/kgsubcutane- ously.Byeitherroute,16,16-dimethylPGE,wasap- proximately500timesmorepotentthanPGE,. OnsetofActionandDurationofAction WhenPGE,wasgivenatthesametimeasab- soluteethanol,thenumberofgastriclesionswasre- ducedby34%(14.5lesionsincontrols,9.6lesionsin PGE,-treatedanimals,justbelowstatisticalsignifi- cance)(Figure7).WhenPGE,wasgivenfrom1 to30 minbeforeethanol,theinhibitionwasnearlycom- plete(85-97%).Theonsetofcytoprotectionafter subcutaneousadministrationofPGE,waslonger: ThePChadtobegiven2.5minbeforeethanoltore- ducethenumberofgastriclesionsbyhalf.Nearto- talinhibition(88-100%)wasachievedwhenitwas GASTRI CLESI ONS 56 B z4 2 . ; ' . . . .. ; . . . .. "0.. - s - i y/ I I \ 0. 05I 0. 1 0. 150. 30. 51. 5,0. 025 0. 03 16. WOI METHYLPGE2: pg/ kg ORALLY,30 MI NBEFORENECROTI ZI NGAGENT Figure5.Cytoprotectionof16,16-dimethylPGE,againstfivedif- ferentnecrotizingagents.16,16-DimetbylPGE,was givenorally30minbeforethenecrotizingagents(1ml ofeitherabsoluteethanol,0.6NHCl,0.2NNaOH,25% NaCl,orboilingwater).Theverticalaxisshowstheav- eragenumberoflesionsperstomachineachgroup.For eachnecrotizingagent,16,16-dimethylPGE,reduced thenumberoflesionsandthedegreeofprotectionwas dosedependent.Tentosixteenratsperpoint. GASTRI CLESI ONS 100 16. 16. LI tMETHYL PGE2PGEz pdkg Figure6.GastriccytoprotectionofPGE,and16,16-dimethyl PGE,againstabsoluteethanol:comparisonoforaland subcutaneousadministration.Theprostaglandinswere given30minbeforeoraladministrationof1mlofabso- luteethanol.Theverticalaxisshowstheaveragenum- beroflesionsperstomachin eachgroup,expressedas percentofcontrols(controlanimalsreceivedethanol butnoprostaglandin).Eachprostaglandinwas3-4 timesmorecytoprotectiveafteroralthanaftersubcuta- neousadministration.Tenanimalsperpoint. September1979 GASTRICLESIONS P 100- 60- 6_ E 5 60 - ii_ I- t g40- i!i 20- 3,PGE2 \Subcutaneously , 12.5510153060120180300 Figure7. MINUTESBEFOREETHANOL 90150240 Timeofonsetanddurationofactionofcytoprotection byPGE,.PGE,,500&kg,wasgiveneitherorallyor subcutaneously,eitheratthesametime(Time0)asab- soluteethanol(Imlorally)oratvarioustimeintervals beforeabsoluteethanol;thesetimeintervalsareshown onthehorizontalaxis.Afteroraladministration,cyto- protectionwasalmostimmediate.Aftersubcutaneous administration,cytoprotectionwasapparentat-2.5 minandmaximalat-30min.Thedurationofaction wasabouttwiceaslongafteroralthanaftersubcuta- neousadministration.Tentotwenty-fiveratsperpoint. injected15-60minbeforeethanol(Figure7).Cyto- protectiondiminishedwhenPGE,wasgivenlonger than1 hrbeforeethanol.Gastriclesionshadre- turnedto50%ofcontrolvalues4hrafteroraladmin- istrationofPGE,,andabout2hraftersubcutaneous administration,asdeterminedbygraphicinter- polationonaplotofthetimeonalogscale, EffectoftheVolumeofDiluent PGE,givenatalowdose(10pg/kg)wasmore GASTRICCYTOPROTECTIONBYPROSTAGLANDINS439 GASTRICLESIONS 100- 80- 20- CONTROL0.5120.512 MLOFDILUENT DOSEOFPGE:,top9lk925p9/k9 ml 0.512 100p9lk9 Figure8Effectofthevolumeofdiluentonthecytoprotectiveac- tivityofPGE,.PGE,(atthreedoselevels)wasgiven orallyineither0.5,1.0,or2.0ml,30minbeforeabsolute ethanol.Thedilutionfactorplayedaroleonlyatthe lowestdose.NS=Notstatisticallysignificantwhen comparedtocontrolgroup.*=P
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