Effects of Leukotrienes on Gastric Acid and Alkaline Secretions

Transcription

1 GASTRONTROLOGY 1987;92: ffects f Leuktrienes n Gastric Acid and Alkaline Secretins S. J. KONTURK, J. BILSKI, A. DMBINSKI, A. WARZCHA, G. BCK, and H. JNDRALLA Institute f Physilgy, Academy f Medicine, Krakw, Pland, and Pharma Synthese Department, Hechst, Frankfurt, Federal Republic f Germany This study was designed t determine the influence f 1euktriene C 4 n gastric acid and alkaline secretin. Leuktriene C 4 was fund t be a ptent inhibitr f gastric acid secretin induced in vagally innervated and denervated prtins f the stmach f cnscius dgs by a variety f stimulants such as histamine, pentagastrin, and meat feeding. Leuktriene C 4 was als an effective inhibitr f acid frmatin in the islated gastric glands stimulated by histamine r dibutyryl cyclic adensine mnphsphate withut r with additin f indmethacin, indicating that this cmpund acts directly n the parietal cells withut mediatin f endgenus prstaglandins. Leuktriene C 4 was als an effective stimulant f gastric alkaline secretin. Hwever, this effect was prbably mediated by an increase in the generatin f endgenus prstaglandin, as it was accmpanied by an increase in the luminal release f prstaglandin z and indmethacin prevented bth the stimulatin f alkaline secretin and luminal prstaglandin z release by 1euktriene C 4 Leuktrienes (LTs) are nvel cmpunds that derive frm arachidnic acid via the lip xygenase enzymatic pathway (1). Recent studies have shwn that sme f these lipxygenase prducts, particularly cystein-cntaining L TC4, are generated by the nrmal gastric mucsa (2) and exert a pwerful influence n gastric micrcirculatin leading t a reductin in mucsal bld flw (3). As LTC4 frmatin in the gastric mucsa was fund t be increased after mucsal damage with ethanl, it has been speculated that increased LT frmatin may be invlved in Received June 19, Accepted Nvember 4,1986. Address requests fr reprints t: Prf. Dr. S. J. Knturek, Institute f Physilgy, Krakw, ul. Grzegrzecka 16, Pland. This study was supprted in part by research grant 501/C/5/M frm the Plish Academy f Science by the American Gastrenterlgical Assciatin /87/$3.50 the ethanl-induced changes in gastric micrvasculature, such as stasis and plasma leakage, leading t the mucsal damage (2). Althugh the changes in gastric mucsal bld flw are knwn t playa supprtive and permissive rle in gastric acid secretin (4), little infrmatin is available regarding the influence f L Ts n gastric secretry activity. Magus et al. (5) reprted that synthetic LTC4 and L TD4 may stimulate acid frmatin in the islated rabbit parietal cells withut interacting with histamine r carbachl. In cntrast, Pendletn et al. (6) reprted that LTs d nt affect gastric acid secretin in cat stmach r in vitr islated rabbit gastric glands but stimulate pepsin secretin. This study was undertaken t determine the influence f pure synthetic L TC4 n gastric acid and alkaline secretin in cnscius dgs and n acid frmatin in in vitr islated rabbit gastric glands. Materials and Methds Gastric Acid Secretin Gastric acid secretin was studied in 6 dgs (grup A), weighing kg and prepared with Thmas gastric fistulas (GFs) and denervated puches f the fundic gland area (Heidenhain puch, HP). xperiments were started abut 1 m after surgery. The animals were deprived f fd but nt water fr a minimum f 18 h befre each test. Animals were used n mre than twice a week. Thrughut all tests except thse with feeding, the GF was left pen t allw drainage f the gastric juice. Secretins frm the GF and HP were cllected cntinuusly and divided int 15-min aliquts; the vlume was measured and acid cntent in each sample was determined and presented as 15-min r 3D-min utputs. Acid secretin was stimulated by Lv. infusin f histamine (80 JLg/kg. h), pentagastrin (8 JLg/kg. h), r by meat Abbreviatins used in this paper: AP, aminpyrine; GF, gastric fistula; HP, Heidenhain puch; LT, leuktriene; PG, prstaglandin; HPLC, high-pressure liquid chrmatgraphy.

2 1210 KONTURK T AL. GASTRONTROLOGY Vl. 92, N.5, Part 1 feeding. Nrmal saline was infused intravenusly thrughut the experiments and when the secretry rate reached a plateau, pure synthetic LTC4 was added t Lv. infusin, the dse being dubled every 30 min and ranging frm 0.5 t 2.0 JLg/kg h. As LTC was disslved in methanl (1000 JLg/ml), in cntrl tests with histamine (80 JLg/kg. h), methanl was added t Lv. infusin in the same amunts (0.5-2 JLllkg. h) and at the same time as in tests with LTC4. The tests with histamine with and withut L TC4 were repeated after pretreatment with indmethacin (2.5 mg/kg) injected intravenusly in a single blus dse befre the start f the tests. In tests with pstprandial secretin, bvine meat (500 g) was given and usually entirely cnsumed. Acid secretin was cllected nly frm the HP and when acid secretry rate reached a plateau, L TC4 was added t Lv. infusin fr a I-h perid in a cnstant dse f 1 JLg/kg. h. In tests with tpical applicatin f L TC4 t the HP mucsa, acid secretin frm the HP was measured by the methd f acid titratin with 10 mm NaOH at an endpint f ph 7, perfrmed utside the puch (7). Acid secretin was stimulated by a cnstant dse f histamine (80 JLg/kg. h) and when the secretry rate plateaued (usually after h), LTC4 was added t the irrigatin fluid f the HP in gradually increasing cncentratins (2.5, 5, and 10 JLg/ml). In cntrl tests histamine alne withut L TC4 was used thrughut the study. Gastric Alkaline Secretin Gastric alkaline secretin was examined in 6 dgs (grup B), weighing kg and equipped with GFs and dudenal fistulas placed in the mid dudenum. A cuff f Dacrn mesh was placed arund the mst prximal prtin f the dudenum just beynd the pylric sphincter. After abut 2 m f recvery frm surgery, the animals were fasted fr 18 hand ranitidine (Glax, Ware, U.K.) was given intravenusly in a dse f 10 mglkg at the beginning f the experiment t suppress gastric acid secretin. A Fley catheter was pulled (by a plyethylene string left between the GF and dudenal fistula) frm the GF int the upper dudenum and inflated (with abut 20 ml f water) t cclude the prximal dudenum 'and thus t prevent any escape f gastric cntent int the dudenum. The catheter was brught t the utside thrugh the GF. A small plyethylene tube (OD 1.5 mm) attached t the catheter was used t perfuse the stmach with saline adjusted t ph 6 and cntaining phenl red as a nnabsrbable marker (40 JLg/ml). Gastric perfusate was cllected frm the GF thrughut the experiment, and the cntent f HC0 3 - in the perfusate was determined every 15 min by back-titratin f the samples t initial ph value with 50 mm HCl using a ph-stat assembly (8,9). Phenl red cncentratin was measured spectrphtmetrically at 520 nm after being alkalinized t ph Marker dilutin and recvery rates were taken int accunt fr the calculatin f gastric HC0 3 - utput as described befre (10). The average gastric recvery was abut 97% (range 92%-100%). Samples f the gastric perfusates were saved at - 20 C fr further determinatins f prstaglandin 2 (PG2) cn- centratins by radiimmunassay using cmmercially available PG2 kits (NN Research Prducts, Bstn, Mass.) as described befre (11). ffects f Leuktriene n Gastric Acid Secretin In Vitr These effects were studied using islated gastric glands prepared frm rabbit fundic mucsa as described by Berglindh et al. (12,13). Briefly, male albin rabbits (3 kg), fasted fr 24 h, were used. The gastric vasculature was perfused under pressure with xygenated phsphatebuffered saline. The mucsa f the fundic prtin f the stmach was separated, minced, and then digested with cllagenase fr min t btain the islated fundic glands. The uptake f [14C]aminpyrine ([14C]AP) was used as an index f the acid frmatin within the glands as described (13). The rati f AP accumulatin in the intraglandular water divided by. the amunt f AP remaining in the medium was calculated in each series f experiments. The rate f acid frmatin in the gastric glands was expressed either in terms f rati values r as the percentage f basal AP rati, which was taken as 100%. Several series f tests were perfrmed using unstimulated gland preparatin and that after histamine r dibutyryl cyclic adensine mnphsphate stimulatin withut aud with additin f indmethacin (10-5 M). Leuktriene C4 was added t the incubatin medium in varius cncentratins ranging frm 10-5 t 10-8 M. In tests with basal and meat meal-stimulated secretin, bld samples were withdrawn befre and at min intervals after LTC administratin fr determinatins f plasma gastrin by specific radiimmunassay using antibdy t gastrin (antibdy 4562 kindly supplied by J. F. Rehfeld, Aarhus, Denmark) at a final cncentratin f 1:100,000. With this antibdy, all majr frms f gastrin were measured at nearly equimlar basis. The system was sufficiently sensitive t detect 5 pg/ml f serum gastrin. The synthesis f L TC4 was carried ut in ur department (Pharma Synthese Department, Hechst AG, Frankfurt, F.R.G.) and the purity f LTC was assessed by high-pressure liquid chrmatgraphy and ther rutine analytic criteria. Leuktriene C4 was supplied as ptassium salt in methanl slutin (1000 JLg/ml) in glass ampules with septum under argn and stred at -20 C. Results are expressed as mean ± SM. The difference in values between grups and between dses was calculated by analysis f variance, p < 0.05 being regarded as statistically significant. Results ffects f Leuktriene C 4 n Gastric Acid Secretin in Cnscius Dgs Leuktriene C 4 infused intravenusly in graded dses ( ILg/kg. h) reduced dse-dependently histamine-induced acid secretin bth frm the GF and HP. The inhibitin frm the GF ccurred almst immediately after the start f LTC 4 infusin and reached abut 80% f the cntrl level in the

3 May 1987 LUKOTRINS AND GASTRIC SCRTION c 's 4.0 ;- < HIS TAM I N (80 g/kg-h) LTC 4 (g/kg-h), 0.5 l t' l 2.0 r:: :t:tltc 4 --HISTAMIN+INDO - HISTAMIN+INDO+LTC min PRIODS Figure 1. ffects f LTC. infused intravenusly in graded dses n histamine-induced gastric acid secretin frm the GF in tests with and withut pretreatment with indmethacin. Mean ± SM f six tests n 6 dgs with GF and HP. Asterisks indicate significant (p < 0.05) decrease belw the cntrl values btained in tests with histamine (withut r with indmethacin) withut LTC. secnd 15-min perid f infusin. With further increase in the dsage f L TC4 t 1 JLglkg. h, the inhibitin was f similar degree but at a dse f 2 JLg/kg. h, and the acid utputs frm the GF were significantly lwer than thse bserved at 0.5 JLglkg. h (Figure 1). The patterns f acid secretin frm the HP in tests with histamine alne and with histamine cmbined with LTC were similar t thse frm the GF. Significant inhibitin f the HP acid respnse t histamine started at a dse f 0.5 JLglkg. h f LTC. With increasing dses f LTC, there was further dse-dependent reductin in this acid respnse. Upn withdrawal f L TC4 infusin, there was an immediate rise in acid utputs t abut 50% f the cntrl level in the secnd 15-min perid and t a level nt significantly different frm the cntrl value in the follrth 15-min peid. After pretreatment with indmethacin, acid respnses frm the GF and HP were significantly higher than thse in tests withut indmethacin, but the inhibitry effect f LTC4 n acid utput was unchanged. After withdrawal f LTC4 infusin, the histamine-induced acid secretin frm the GF and HP tended t return tward the cntrl level, but it was significantly lwer than the cntrl vaille thrughut the pst,infusin perid (Figure 1). Leuktriene C4 infused intravenusly in graded dses was als an effective and dse-dependent inhibitr f pentagastrin-induced acid secretin frm the GF and HP (Figure 2). When given during pstprandial secretin, LTC4 reduced significantly acid utput frm the HP withut affecting serum gastrin level (Figure 3). In tests with intrapuch titratin, histamine- c: 's " PNTAGASTRIN (8 g/kg-h) LTC4 (ljg/kg-h) 0.5 '" min PRIODS Figure 2. ffects f LTC. infused intravenusly in graded dses n pentagastrin-induced acid secretin frm the GF and HP. Mean ± SM f six tests n 6 dgs with GF and HP. Asterisks indicate significant (p < 0.05) decrease belw the cntrl values with pentagastrin alne. induced acid utputs averaged abut 2.15 ± 0.26 mm1l15 min and this level was well sustained thrughut the experiment. The additin f L TC4 in graded dses ( JLg/ml) t the HP perfusin fluid failed t affect significantly the histaminestimulated acid secretin. ffects f Lellktriene C 4 n Acid Frmatin in Islated Rabbit Gastric Glands Islated gastric glands accumulated [14C]AP in the absence f added secretaggues. The mean 0.6 c: 's ( min PRIODS Figure 3. ffects f LTC. infused intravenusly in a cnstant dse n meal-induced acid secretin frm the ffp and serum gastrin level. Mean ± SM f six tests n 6 dgs with GF and HP. Asterisks indicate significant (p < 0.05) decrease belw the cntrl values with feeding alne. r

4 1212 KONTURK T AL. GASTRONTROLOGY Vl. 92, N.5, Part 1 Table 1. ffects f Leuktriene C 4 Added in Varius Cncentratins t the Incubatin Medium n Aminpyrine Rati in the Islated Rabbit Gastric Glands 10-8 Basal 20 ± 1 20 ± 2 Histamine 10-5 M 68 ± 7 53 ± 11 a DBcAMP 10-' M 66 ± 7 45 ± 6 0 AP rati fr LTC. (M) 19±2 18±2 17±l a 50 ± 6 a 50 ± 7" 49 ± 8 a 40 ± 6 a 38 ± 6 a 40 ± 5 a DBcAMP, dibutyryl cyclic adensine mnphsphate; LTC., leuktriene C 4 Values are mean ± SM f 10 tests. 0 Significant (p < 0.05) decrease belw the value btained in tests withut leuktriene. (± SM) basal AP rati in ur experiments was abut 20 ± 2. Leuktriene C 4 added t the incubatin medium at cncentratins ranging frm 10-8 t 10-6 M failed t affect significantly the AP rati. At a cncentratin f 10-5 M, LTC 4 caused a small but significant reductin in basal AP uptake (Table 1). When histamine was used at a cncentratin f 10-5 M, the AP accumulatin was abut twice as high as in the unstimulated glands. Leuktriene C 4 added t the incubatin medium resulted in a significant fall in the histamine AP rati starting with a cncentratin f 10-7 M, but n significant difference in this fall was bserved with further increase in L TC 4 cncentratins. Leuktriene C 4 used in the highest cncentratin reduced significantly histamineinduced AP accumulatin at all cncentratins f histamine, except the highest ne, when n difference was fund in the AP accumulatin between the tests with and withut LTC 4 (Figure 4). Dibutyryl cyclic adensine mnphsphate increased the AP rati t a similar extent as histamine. This rati was als significantly reduced by L TC 4, but this reductin did nt depend n the cncentratin f LTC 4 used (Table 1). Leuktriene C 4 added at i5 BASAL DBcAMP (M) Figure 5. ffects f L TC 4 added t the incubatin medium in a cnstant cncentratin n the AP rati in rabbit gastric glands stimulated by gradually increasing cncentratins f dibutyryl cyclic adensine mnphsphate (DBcAMP). Mean ± SM f 10 tests. Asterisks indicate significant (p < 0.05) decrease belw the cntrl values btained with dibutyryl cyclic adensine mnphsphate alne. a cnstant cncentratin t the incubatin medium f glands stimulated by gradually increasing cncentratins f dibutyryl cyclic adensine mnphsphate als reduced dibutyryl cyclic adensine mnphsphate-stimulated AP accumulatin at all cncentratins except the highest ne (Figure 5). Additin f indmethacin t the incubatin medium did nt prevent the LTC 4 -induced decrease in basal and histamine- r dibutyryl cyclic adensine mnphsphate-stimulated acid frmatin in the islated glands (Figure 6). ffects f Leuktriene C 4 n Gastric Alkaline Secretin and Prstaglandin Release Leuktriene C 4 infused intravenusly in graded dses prduced a dse-dependent increase in alkalin) secretin, reaching abut 400 JLml/30 min UNSTIMULATD GLANDS 40 a. 20 SAL I a: Q '10-5 HISTAMIN (M) Figure 4. ffects f LTC. added t the incubatin medium in a cnstant cncentratin n AP rati in the islated gastric glands stimulated by gradually increasing cncentratins f histamine. Mean ± SM f 10 tests. Asterisks indicate significant (p < 0.05) decrease belw the cntrl values btained with histamine alne. Figure 6. The AP rati in resting and histamine- r dibutyryl cyclic adensine mnphsphate (DBcAMP)-stimulated gastric glands withut and with additin f indmethacin, LTC, r their cmbinatin int the incubatin medium. Mean ± SM f 10 tests. Asterisks indicate significant (p < 0.05) decrease belw the cntrl values.

5 May 1987 LUKOTRINS AND GASTRIC SCRTION 1213 C C\.. N... \.::J a <5 -=200 'm u D.2S I 1.0. r S min PRIODS Figure 7. ffects f LTC infused intravenusly in graded dses n luminal release f PG 2 and alkaline secretin frm the GF in dgs pretreated with ranitidine (t suppress acid secretin) withut r with indmethacin. Mean ± SM f five tests n 5 dgs with gastric and dudenal fistulas. Asterisks indicate significant decrease belw the cntrl values btained with L TC 4 alne. at a dse f 2.0 ILg/kg h. It was accmpanied by a gradual increase in PG 2 release int the gastric lumen (Figure 7). Bth f these effects were cmpletely ablished by pretreatment with indmethacin, which als reduced basal alkaline secretin frm the stmach. Discussin This study prvides evidence that L TC 4 is a ptent inhibitr f gastric acid secretin and an effective stimulant f gastric alkaline secretin in dgs. S far, n systematic studies have been undertaken t determine the influence f LT n gastric secretin. Pendletn et al. (6) reprted that LTs f the C, D, and series did nt affect gastric acid secretin but reduced the ptential difference value, suggesting that they may cause mucsal damage. Accrding t ur findings, L TC 4 caused a ptent and dsedependent inhibitin f gastric acid respnses t exgenus stimulants such as histamine and pentagastrin and endgenus stimulants such as meat feeding. We have n explanatin fr the discrepancy between ut results and thse reprted by thers (5,6). The fact that LTC 4 was capable f inhibiting the secretry activity f the fully innervated and vagally denervated prtins f the stmach indicates that vagal nerves are nt invlved in this inhibitin. Our bservatin that L TC 4, given in a rather small dse (1.0 ILglkg. h), inhibited gastric acid respnse t meat feeding suggests that the agent is capable f suppressing physilgic stimulatin f gastric secretin invlving gastrin, chlinergic reflexes, and ther mechanisms. Because serum gastrin respnse t this stimulatin was nt significantly altered, it may be expected that the agent des nt influence the release f gastrin but instead nly prevents its stimulatry actin n the parietal cells. In this respect, L TC 4 is different frm PG 2 r its stable analgues, which were reprted t reduce pstprandial gastrin release (14). Anther difference is that LTC 4 is inactive when applied tpically t the gastric mucsa, whereas PG 2 was reprted t inhibit gastric acid secretin (14). It is likely that LTC 4 is mre labile as cmpared with PG 2 and is the subject f quick degradatin after expsure t the gastric mucsij.. The fllwing questin arises: what is the mechanism f the inhibitry actin f L TC 4 n gastric acid secretin? The fact that LTC 4 is a ptent vascnstrictive agent suggests that the bserved inhibitin results, at least in part, frm the limitatin f the mucsal bld flw. The pssible rle f vascnstrictin in the bserved inhibitin f gastric acid secretin by LTC 4 is supprted by previus studies (3) shwing a pwerful influence f this agent n gastric micrcirculatin. The prpsitin that LTC 4 acts directly n acidsecreting cells is supprted by in vitr studies shwing that this agent inhibited acid frmatin by the islated rabbit gastric glands. Leuktriene C 4 reduced slightly basal and inhibited histamine- r dibutyryl cyclic adensine mnphsphate-stimulated acid frmatin by the glands. This favrs the idea that L TC 4 reduces acid secretin thrugh an inhibitin f adenylate cyclase but that it may als act at a site distal t the cyclic adensine mnphsphate system (15). As the blckade f PG generatin by indmethacin in cnscius dgs r in vitr islated parietal cells did nt influence the inhibitry activity f L TC 4, it may be assumed that endgenus PGs are nt invlved in the bserved gastric acid inhibitin. A similar, mechanism f actin n acid secretin has been prpsed fr PG 2, which was reprted t inhibit bth histamine- and cyclic adensine mn phsphate-induced acid prductin in islated rabbit gastric glands (16). Leuktriene C 4 was als an effective stimulant f gastric alkaline secretin. Hwever, this effect was prbably mediated by secndary release f mucsal PG, as it was accmpanied by an increase in the luminal release f PG and indmethacin prevented bth the stimulatin f alkaline secretin and luminal release f PG. Unlike in previus studies

6 1214 KONTURK T AL. GASTRONTROLOGY Vl. 92, N.5, Part 1 (2,5), we fund little evidence fr the damaging actin f L TC 4 n gastric mucsa. The increase in alkaline secretin des nt seem t result frm the mucsal damage and subsequent passive HC0 3 transudatin frm the bld int the gastric lumen but prbably represents a genuine stimulatin f alkaline secretin mediated by PG. The absence f mucsal damage by the LTC 4 is als supprted by the return f acid secretin t the pre-ltc 4 level when the infusin f cmpund was stpped in in viv canine experiments. A similar mechanism f alkaline secretin t that induced by LTC 4 was prpsed befre fr the stimulatry effect f tpical acid where mucsal PGs were als fund t mediate the alkaline secretin (11,17,18). It remains t be determined whether r nt LTs, which were fund t be generated by gastric mucsa (3), cntribute t the mucsal alkaline secretin by physilgic stimulants such as gastric acid r a gastric meal. References 1. Samuelssn B. Leuktrienes: mediatrs f immediate hypersensitivity rea.ctins and inflammatin. Science 1983;220: Peskar BM, Lange K, Hppe U, Pesker BA. thanl stimulates frmatin f leuktriene C in rat gastric mucsa. Prstaglandins 198(>;31: Whittle BJR, Oren-Wlman N, Guth PH. Gastric vascnstrictr actins f leuktriene C, PGF 2 and thrmbxane mimetic U n rat submucsal micrcirculatin in viv. Am J PhysiI1985;248:G Guth PH, Ballard KW. Physilgy f the gastric circulatin. In: Jhnsn LR, ed. Physilgy f the gastrintestinal tract. New Yrk: Raven, 1981: Magus R, Bali J-p, Rssi J-C, Girard JP. Leuktrienes stimulate acid secretin frm islated gastric parietal cells. Bichem Biphys Res Cmmun 1983;14: Pendletn RG, Shepherd AI. Stavrski JM. Leuktriene effects upn the transgastric ptential difference and pepsin secretin. ur J Pharmacl 1986;123: Knturek SJ, Cieszkwski M. Kwiecien N, Harrisn C. Gastric respnse t tpical and intravenus histamine and tpical histamine and tpical H 2 -receptr blckade in dgs. Agents Actins 1981;11: Knturek S1. Tasler I. Bilski J. Prstaglandins and alkaline secretin frm xyntic, antral and dudenal mucsa. Am J PhysiI1983;245:G Swierczek JS, Knturek SJ. Gastric alkaline respnse t mucsa-damaging agents: effect f 16,16-dimethyl prstaglandin 2 Am J PhysiI1981;241:G Blm DS, Jacbsn D, Grssman MI. Validatin f dilutin indicatrs in the stmach. Gastrenterlgy 1967;52: Knturek SJ, Bilski I. Tasler I. et al. Rle f endgenus prstaglandins in dudenal alkaline respnse t luminal hydrchlric acid r arachidnic acid in cnscius dgs. Digestin 1986;34: BergliJ,ldh T, Obrink KJ. A methd fr preparing islated glands frm the rabbit gastric mucsa. Acta Physil Scand 1976;96: Berglingh T, Helander HT, Obrink KJ. ffect f secretaggues n xygen cnsumptin, aminpyrip.e accumulatin and mrphlgy f islated gastric glands. Acta Physil Scand 1976;97: Rbert A. Prstaglandins and the gastrintestinal tri\ct. In: Jhnsn LR, ed. Physilgy f the gastrintestinal tract. New Yrk: Raven, 1981: Sachs G, Berglindh T. Physilgy f the parietal cells. In: Jhnsn LR, ed. Physilgy f the digestive tract. New Yrk: Raven, 1981: Nylander 0, Berggvist, Obrink KJ. ndgenus prstaglandins mdulate stimulatin f acid frmatin in islated gastric glands. In: Allen A, ed. Mechanisms f mucsal prtectin in the upper gastrintestinal tract. New Yrk: Raven, 1984: Haylings JR, Garner A. Influence f luminal acidificatin n bicarbnate transprt by gastric and dudenal islated mucsa. Prstaglandins 1981;21(Suppl): Knturek SJ, Bilski I. Tasler J. Gastrdudenal alkaline respnse t acid and taurchlate in cnscius dg. Am J Physil 1984;247:G