Aomeprazole Su cia en

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To xr co to ~i c ATHOLOGYSSN09 12-6233Copyright 0 1988 by the Society ofToxicologic P athologists Volume 16, Number 2, 1988Piinled in U.S.A.

Omeprazole: Its Influence on Gastric AcidSecretion, Gastrin and ECL Cells*HAKANLARSSON,OLFHAKANSON,~ILLEVI ATTSSON,IRGITTA YBE RG,FRANK UND LE R,~ND ENARCARUSON

Department of Biology, AB H assle, Molndal, Sweden. andDepartnients of Pharm acology and Histology,, University of Ltind, Ltind, SwedenABSTRACT

The H+,K+-ATPase nhibitor omeprazole is a highly effective gastric antisecretory agent, both in animalsand man, with a long duration of action. These properties are shared by a number of recently describedhistamine H,-receptor antagonists. In life-long oncogenicity studies of these H,-receptor antagonists, as wellas with the H+,K+-ATPase nhibitor omeprazole, gastric enterochromaffin-like cell (ECL cell) hyperplasiaand carcinoids have been found. The purpose of this paper is to summarize available evidence for theGastrin Hypothesis to explain the development of ECL-cell hyperplasia. The hypothesis may be outlinedas follows: 1) Inhibition of gastric acid secretion leads to elevated antral pH and, secondarily, to release ofgastrin from the antral gastrin cells into the blood stream. 2) Gastrin causes both general hypertrophy of theoxyntic mucosa and hyperplasia of the ECL cells in the oxyntic mucosa. That this sequence of events occursnot only with omeprazole but also with other effective gastric antisecretory agents has been verified in therat by giving the H,-receptor antagonist ranitidine as a continuous infusion. Ranitidine caused a hypergas-trinemia of a similar magnitude as that seen after omeprazole, provided that the acid secretion was inhibitedto a similar degree. At similar gastrin levels, ECL-cell hyperplasia of the same magnitude developed duringboth ranitidine and omeprazole treatment. Antrectomy prevented the development of ECL-cell hyperplasiaduring omeprazole treatment, indicating that the hyperplasia was not due to the drug treatment per se, butrather to the hypergastrinemia. Both the hypergastrinemia and the ECL-cell hyperplasia were found to bereversible. Control plasma gastrin levels were reached within a few days of stopping long-term treatment,and the ECL-cell density was back to normal 20 weeks after discontinuing 10weeks of treatment with high-dose omeprazole. We conclude from these studies that the ECL-cell hyperplasia seen in rats after long-termtreatment with gastric acid secretion inhibitors is reversible and secondary to the hypergastrinemia, and isnot caused by the drugs per se. Furthermore, although the gastrin mechanism for the regulation of theECL cells seems to be similar in different species, there are quantitative differences with regard to the ECL-cell density and possibly also the sensitivity of ECL cells to gastrin.

BACKGROUNDWith the development of substituted benzimid-azoles, an entirely new p rinciple for reducing gastric

acid secretion was introduced. Inh ibition is achievedby direct interaction with the proton pump, theenzyme H+,K+-ATPase, n the parietal cell. In thesearch for new and be tter compo unds for use in thetreatment of peptic ulcer and related d iseases, pro-ton-pump inhibitors such as omeprazole may proveto constitute a major break-through, comparablewith that of the invention of histamine H,-receptorantagonists.Th e av ailability of highly effective antisecretory* Presented at the S ixth International Symposium of the So-

ciety of Toxicologic Pathologists: Gastrointestinal ToxicologicPathology,June 1-3, 1987 in Philadelphia, Pennsylvania.

agents also focuses attention on the fact that acid inthe stom ach serves to restrain the release of gastrinfrom gastrin cells in the an tral mucosa. A part froma stimu latory action o n gastric acid secretion, gastrinis known for its general troph ic action on the oxynticmucosa (13, 14), and it seems to be involved in theregulation of the activity and num ber of the entero-chromaffin-likeD(ECL)cells (10, 15). The ECL cells,which are peptide hormone-producing cells, arepresent solely in the oxyntic mucosa. The ir functionis unknown, in the sense that the peptide hormon ethey produce has not yet been identified. However,th e ECL cells are active in the prod uction an d stor-age of histamine and are known to be under thecontrol o f gastrin (9). Based on this knowledge, it isnot su rprising that long-term (2 years) treatment ofrats with po tent long-acting inhibito rs ofgastric acid

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268 LARSSON ET AL TOXICOLOGICATHOLOGY% inhibi t ion

II12 24 36 40

lo01dm A ,I IME(hours)FIG.1.-Duration of action of omeprazole in the rat.Omeprazole was given orally (40 and 40 0 pmoVkg) oncedaily for 3 days and the gastric acid secretion was mea-sured at 6-hour intervals for up to 48 hours after the lastdose. Acid secretion was stimulated by a sc infusion of amixture of pentagastrin (20 nmol x kg-I x hour-) andcarbachol(l10 nmol x kg-l x hour-) for 2 hours. Detailsare given in ref. 26.

secretion caused a diffuse ECL-cell hyperplasia,which, in some individuals, developed into focalhyperplasia an d ca rcinoids (1 2).In this paper, the inhibitory action of omeprazoleon gastric acid secretion in the ra t will be described.In ad dition, we will present experimental evidence,obtained both w ith omeprazole and with ranitidine,in favor of the Gastrin Hypothesis, which pos-tulates that the ECL-cell hyperplasia observed afterlong-term treatment with powerful anti-secreta-gogues is a result of th e ensuing hypergastrinemia.

THEGASTRIN YPOTHFSISInhibition of Gastric Acid Secretion. Extensiveresearch has revealed the mechanism behind theantisecretory action of omeprazole (1 8, 23-25).Three main steps lead to the very selective inhibi-tion of the proton-pumping enzyme H+,K+-ATPase:1) Owing to its weak-base pro perties (its pk, is 4.0),

omeprazole will be protonated at a low pH. Sincethe charged molecule will penetrate the plasmamem brane only with great difficulty, it will concen-trate in the acid com partm ents of the parietal cellsin the gastric mucosa. 2) Protonation will lead totransformation of the omeprazole molecule to anactive form. A prerequisite for this transform ationis the acid environment with the subsequent pro-tonation o f the molecule. Therefore, ome prazole willonly be activated at places where there is a suffi-ciently low pH (i.e., below the pk3. 3) Thus, ome-prazole is activated in the imm ediate vicinity of,and will subsequently bind to, the H+,K+-ATPase.This leads to an inhibition of the enzyme without

affecting other ion movements in the apical mem-bra ne o f th e par ietal cell (1 7, 25).The steps presented above are prerequisites forinhibition, a nd all these condition s are met only inthe parietal cell in the stomach. Since the secretorycanaliculi of the parietal cell in the stomach is theonly place in the body where such a low pH (1-2)is found, this concept of inhibition of gastric acidsecretion represe nts a very selective way of reducinggastric acidity in the treatm ent of p eptic ulcer dis-ease.In th e rat, o meprazole is a very effective inhibitorofgastric acid secretion; it has an oral ED,, of aroun d10 pmol/kg (single dose) (26). After 3 daily oraldoses of 40 pm oVkg, the antisecr etory effect was fol-lowed for up to 48 hours. As can be seen in Fig. 1,the duration of action is long. Complete inhibitionwas recorded for abou t 6 hours, whereafter a gradualdecline of the effect was not ed, so that 24 hou rs afterdose, the inhi bitio n was 20-30%. A t a higher dose(400 pmoVkg), there was complete inhibition foralmost 18 hours. Tw enty-four hours after dose, theinhibition was approximately 70%. The degree ofinhibition of ac id secretion in this study was directlycorrelated to the degree of inhibition of the activityof isolated H+,K+-ATPase(26).Relation Between Acid Iiihibition and Gastrin Re-lease. Plasm a gastrin levels have been determ inedin freely-fed female rats after omeprazole at 40 or400 pm ol/kg given orally for up to 20 weeks (7, 16).After the first dose, there was a rise in plasm a gastrinlevels, which upon prolonged treatment increasedto a steady-state level. Th is may b e a consequenceof the combined effect of an accumulation of th egastric acid inhibitory effect during the first few daysof administration and an antral gastrin-cell hyper-plasia (1). When the maximal level was reached,within approxim ately 2 w eeks, this level was ma in-tained for a t least 20 weeks of treatment (16). Th ehypergastrinemia over 24 hours was dependent onthe degree of acid inhibition (Fig. 2), so that thehighest maximal gastrin levels were found imme-diately after dose, when acid secretion is abolished(doses at or ab ove 4 0 pmol/kg). Twenty-four ,hoursafter dose, the plasma gastrin levels had decreasedin parallel with the decrease in gastric acid antise-cretory effect. Thds, there was a direct relationshipbetween the degree of inhibition of gastric acid se-cretion an d the plasma gastrin levels.Now, could a similar degree of gastrin release beinduced by othe r inhibitors of gastric acid secretionbesides omeprazole? To investigate this, the H,-re-ceptor antagonist ranitidine was given to rats bycontinuous sc infusion s (1 25-1,700 pm ol x kg-I xday-), using osmotic minipumps. Th e results werecom pared with those after oral daily doses of ome-


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Vol. 16, No. 2, 1988 GASTRIN AN D ECL CELLS 269Acidsecretion% inhibition

Gastrinpglml100

-1 :100140 125 40 0 Controlpmollkg, day 40 125 400pmollkg, day0 hours after 24 hours afterlastdose last doseFIG.2.-Correlation between percent inhibition of stimulated (as in Fig. 1) gastric acid secretion (A) and the plasmagastrin levels (B) in rats 2 and 24 hours after the last of 7 daily, oral doses in rats. Means k SEM, n = 5.prazole (10-400 pmol/kg) given for the same periodof time (1 week). Both compounds dose-depen-dently inhibited stimulated gastric acid secretion.Furthermore, dose-dependent increases in plasmagastrin to similar levels were recorded. T he exper-imen t showed that, provided tha t acid secretion wasinhibited to a similar degree, ranitidine is capableof inducin g a hypergastrinemia of a magnitude sim-ilar to that found during omeprazole treatment. Adirect action o n th e gastrin cells by either of thesecom pound s seems less probable after these experi-ments.The idea that the hypergastrinemia is a conse-quence of acid inhibition was furthe r substantiatedby an experiment in which omeprazole was giveni.m. at 10 pmoVkg to fasted rats (21, Fig. 3). Thisdose gives a rapid an d complete inhibition o f acidsecretion. T he do se was given during a co ntinuou sinfusion of either water o r 0.15 M HCl directly intothe stom ach via a gastric cannula. When omeprazolewas given during the water infusion, the plasmagastrin levels doubled. How ever, the intragastric HClinfusion prevented the rise in plasma gastrin, in-dicating that the gastric pH is important for therelease of antral gastrin.General Tropliic Eflects of Hypergastriiieniia.Gastrin is a hormone with several actions. Apartfrom being a po tent gastric acid secretagogue, it h asa general trophic effect on the stoma ch (7 , 13, 14).Thus, hypergastrinemia causes growth of the mu-cosa in the oxyntic gland area. Such increased growthhas also been found during long-term omeprazoletreatment of rats (7, 15, 16). Increases of a similarmagnitude have also been found after long-termtreatment with the H,-antagonists metiamide andcimetidine ( 5 , 1 ).Eflects of Hypergastrinernia on ECL Cells. Hy-pergastrinemia affects the ECL cells. These cells seemto be regulated by gastrin, both with respect to ac-tivity, reflected in their capacity to produce an d re-

lease histamine, and to rate of proliferation. 'Aftervarious types of surgical intervention s in the stom-ach in th e rat, leading to changes in the plasma levelsof gastrin, a causal relationship betw een circulatinggastrin levels and the density of ECL cells in theoxyntic mucosa was postulated by Hdkanson andcowo rkers (9). Such a relationship was also eviden tduring omeprazole and ranitidine treatments (seebelow).Correlation Betweeti Plasma Gastrin arid ECL-Cell Hyperplasia. We found an excellent correla-tion between the plasma gastrin concentration andECL-cell density in the oxy ntic mucosa (Fig: 4) (15 )after both low- and high-dose omeprazole o r rani-tidine treatments in intact rats, and in antrecto-mized rats with or without omeprazole treatment.After high-dose omeprazole treatment for 20 weeksin intact rats, the ECL-cell density increased ap-proximately 5-fold and the ra te ofproliferation seemsto h ave been linear (Fig. 5). It is also important to

I -r200

1000 ontrol

Omeprazole0 10 pmollkg i.m.

Gastric infusion: Water HCI0.15 moll12.25 mllh 2.25 mllhFIG.3.-Prevention of gastrin release by infusion of

0.15 hf HCl into the stomachof fasted rats. Saline (control)or omeprazole (10 pmol/kg)was given i.m. 1 hour afterthe star t of a 3-hour intragastric infusion of either wateror 0.15 hf HCl. Blood foigastrin determinationwas drawnimmediately before (unfilled bars) and 2 hours afteradministration (filled bars). Means f SEM, = 4-7.


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270 LARSSON ET AL TOXICOLOGICATHOLOGYECL cells .Number/visual field600- -

400-

0 lntaCt,COntrol0 Intact, omepraro le 1 0 pmollkg0 Intact, omepraro le 400 p m o l lk g0 Intact, nnltldlne 175+175+350BmollkgAntrectomlzed. control pmoVk gm Antrectomlzed. omeprazole 40 0 pmollkg

200-

04100 200 400 aoo 1600 3200

Gastrln (pg/ml)FIG.4.-Correlation between plasma gastrin levels andoxyntic mucosal ECL-cell density after 10 weeks oraltreatment with omeprazole(lowor high dose) or ranitidinein intact and antrectomized rats. Group means f EM ,

n = 10-11.note that antrectomy (i.e., removal ofthe main sourceof gastrin) completely prevents the proliferation ofECL cells during omeprazole treatment (15). In theantrectomized rats, omeprazole maintained theplasma gastrin levels and the ECL-cell density atcontrol levels (Fig.4).The fact that gastrin remainedin the circulation of these rats might be explainedby the observation that gastrin cells sometimes re-mained: in a border zone along the margin of theretained oxyntic gland area. The maintained gastrinlevels probably prevented the development of ECL-cell atrophy that normally occurs after antrectomy.The findings strongly indicate that the developmentof ECL-cell hyperplasia is not caused by the drugtreatment perse but rather by the hypergastrinemia.Conceivably, a proliferation of ECL cells to thedegree found during omeprazole treatment shouldoccur with any gastric acid secretion inhibitor ofsimilar effectiveness. Thus, when ranitidine was giv-en by continuous sc infusion (1,200 pmol x kg-' xday-') for 4 weeks, using osmotic minipumps, thistreatment resulted in a similar increase in ECL-celldensity as did omeprazole (400 pmoVkg/day, PO)(21) during the same period of time. This argues infavor of the interpretation that the hypergastrine-mia, not the drug treatment, is responsible for thehyperplasia of ECL cells in rats.

REVERSIBILITYIt has been shown after both short- and long-term

treatment with omeprazole that hypergastrinemia israpidly reversible (1 5, 16). Control plasma gastrinlevels are reached within approximately 2-5 daysafter stopping treatment. The oxyntic mucosal ECL-cell density remains high for a longer period of time.After cessation of 10 weeks daily oral treatment with

iim,

10 I S i0 30

FIG. .-Oxyntic mucosal ECL-cell density in rats dur-ing 20 weeks oral treatment with omeprazole at 400 pmoVkg daily. Reversibility of the effect is shown after 10weekstreatment. Both previously vehicle- and omeprazole-treated rats were rechallenged with omeprazole for another10-week treatment period starting after a 10-week recov-ery period. Means f EM , n = 3-10.

T h e (week#)

omeprazole (400 pmolflcg), the ECL cells did notreach normal density until 20 weeks after the lastdose (Fig. 5). Creutzfeldt and coworkers (4) havealso shown a complete (and somewhat more rapid)recovery from the ECL-cell hyperplasia induced inrats by high-dose omeprazole administered for 40days.Another experimental fact showing the revers-ibility of effects on the ECL (and gastrin) cells is thata rechallenge with omeprazole for another 10-weekperiod starting after 10 weeks of recovery yieldedneither plasma gastrin levels (not shown) nor ECL-cell proliferation rates (Fig. 5) different from thosefound in age-matched controI rats. Thus, no irre-versible changes in the gastrin or ECL cells wereinduced by the omeprazole treatment.

SPECIES IFFERENCESNormal ECL-cell density is higher in the rat thanin many other species (8, 12). In mice treated for

18 months with omeprazole, there was no or a verylow degree of endocrine cell hyperplasia and no car-cinoids developed (12). In the dog treated with ome-prazole (80 pm?l/kg, PO) for 1 year, a 50 % or lessincrease in endocrine cell (argyrophil cell) densitywas observed (6) , although this treatment yieldedgastrin levels (22) comparable to those found in therat during high-dose omeprazole treatment. This isto be compared with the 3- and 5-fold increases inECL-cell number seen in rats with a similar degreeof hypergastrinemia after 10 and 2 0 weeks treat-ment, respectively (7, 15) (Fig. 5). That the mecha-nisms involved in the stimulation of ECL-cell pro-liferation are nevertheless similar is suggested by


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Vol. 16, No. 2, 1988 GASTRIN AND ECL CELLS 27 1the fact that antrectomy prevented the proliferationof argyrophil cells in the dog (6).

FURTHERVIDENCEOR THEGASTRINHYPOTHESISIn our view, the evidence presented above is con-

vincing. However, the concept has been questioned.One of the arguments against it is that the achlor-hydria per se or omeprazole could cause prolifera-tion of ECL cells, eventually developing into car-cinoids (20). Since not only omeprazole, but alsoranitidine, induces ECL-cell hyperplasia, it appearsunlikely that the hyperplasia is linked to omeprazoleper se. In fact, it has been shown that pentagastrin(250 pg/kg, sc twice daily for 3 months) given torats results in a considerable increase in the relativenumber of endocrine cells (2), of which the majority(about V3) constitute ECL cells. The endocrine cellhyperplasia induced in these rats was comparableto the hyperplasia found after omeprazole treat-ment, although pentagastrin stimulated acid secre-tion. Thus, proliferation of ECL cells may occurboth in states of hypersecretion and in cases ofachlorhydria. The situation seems to be similar inman, where in rare cases, ECL-cell carcinoids havebeen found in both the Zollinger-Ellison Syndrome,characterized by hypersecretionof acid, and in per-nicious anemia, characterized by achlorhydria (3).In both situations there is hypergastrinemia. Thisindicates that the hypergastrinemia, and not the in-hibition of acid secretion, is the cause of the ECL-cell hyperplasia. Furthermore, very high gastrinlevels were observed in rats in which the oxynticgland area had been partly excised. This was alsoassociated with hyperplasia of ECL cells in the re-maining part of the oxyntic mucosa (1 9). Thus, en-dogenous hypergastrinemia is capable of causingproliferation of the ECL cells without the influenceof exogenously added drugs.

CONCLUSIONSWe find the Gastrin Hypothesis to be a valid

concept, and a sound basis for further experiments.In summary, the most pertinent conclusions fromthe studies referred to are that 1) The ECL-cell hy-perplasia seen in animals after long-term treatmentwith gastric acid secretion inhibitors is secondaryto the hypergastrinemia, and not to the achlorhydriaor to the drug treatment per se; 2) the hypergastri-nemia and oxyntic mucosal ECL-cell hyperplasiaare reversible; and 3) there are species differenceswith respect to the density ofECLcells and probablywith respect to their sensitivity to gastrin.

ACKNOWLEDGMENTSWork presented in this paper was performed atthe Department of Biology, Gastrointestinal Re-

search at AB Hassle, Molndal, Sweden and a t theDepartments of Pharmacology and Histology at theUniversity of Lund, Lund, Sweden. The followinghave contributed skillfully hereto: Kjell Anderson,Marie-Louise Berglund, Kerstin Carlsson, Eva En-gelbert, Jan Fryklund, Herbert Helander, AgnetaKarlsson, Lars Lundell, Gunhild Sundell, LennartSvensson, Eva Varai, and Bjorn Wallmark. Theirwork is gratefully acknowledged.

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The effectsofprolonged ad min istration of large dosesof cimetidine on the gastric mucosa of rats. In: Ci-rnetidine. The Westniinster Hospital Syn iposiuin. CWastell and P Lance (eds). Churchill Livingstone,Edinburgh, pp. 191-206.6. Ekman L, Hanson E, Havu N, Carlsson E, nd Lund-borg C (1985). Toxicological studies with omepra-zole. Seaiid. J.Gastroenterol. Supp l. 10 8) 20: 53-69.7. HAkanson R, Blom H, Carlsson E, Larsson H, RybergB, and Sundler F (1986). Hypergastrinaemia pro-duces trophic effects in stomach but not in pancreasand intestines. Regul. Pept. 13: 223-233.8. Hakanson R, Bottcher G, Ekblad E, Panula P, Si-monsson M, Dohlsten M, Hallberg T, and Sundler F(1986). Histamine in endocrine cells in the stomach.A survey of several species using a panel of histamineantibodies. Histoelternistry 86: 5-1 7.9. HAkanson R, Bottcher G, Sund ler F, an d Vallgren S

(1 986). Activation and hyperplasia of gastrin and en-terochromaffin-like cells in the stomach. Digestion(Suppl. 1) 35: 23-41.1Q. HAkanson R, ?scarson J, and Sundler F (1986). Gas-trin and the trophic control of the oxyntic mucosa.Scund. J . Gastroeriterol. (Suppl. 118) 2 1 18-30.11. Halter F, Inauen W, Eigenmann F, Varga L, and KoelzHR (1 986). Effect of acid inhibition on th e growth ofparietal cells. Scattd. J. Gastroenferol. (Suppl. 125)12. Havu N (1986). Enterochromaffin-likecell carcino idsof gastric mucosa in rats after life-long inhibition ofgastric acid secretion. Digestion (Suppl. 1) 35: 42-55.13. Johnso n LR, Aures D, and HAkansonR (1 969). Effectof gastrin on the in vivo incorporation of 14C-leucine

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272 LARSSON ET AL TOXICOLOGICATHOLOGYinto protein of the digestive tract. Proc. SOC.Exp.Biol. Med. 132: 996-998.14. Johnson LR, Awes D, and Yuen L (1969). Penta-gastrin induced stimulation of protein synthesis inthe gastrointestinal tract. A m . J. Physiol. 21 7: 25 1-254.15. Larsson H, Carlsson E, Mattsson H , Lundell L, Sun-dler F, Sundell G, Wallmark B, Watanabe T, andHAkanson R (1986). Plasma gastrin an d gastric en-terochromaffin-like cell activation and proliferation.Studies with omeprazole and ranitidine in intact andantrectomized rats. Gastroenterology 90: 39 1-399.16. Larsson H, Carlsson E, Ryberg B, Fryklund J, andWallmark B (1988). Rat parietal cell function afterprolonged inhibition of gastric acid secretion. An?.J.Physiol. 254: G 33 43 9 .17. Larsson H and Ryberg B (1983). Omeprazole in-creases K+ et flow during stimulated conditions inthe mammalian gastric mucosa in W o . T he Phys-iologist 26(4): A27.

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secretion in rats on p lasma gastrin levels and de nsityof enterochromaffin-like cells in th e ox yntic mucosa.(Abstr no. 174). In: Proceedings from 6th Interna-tional Syniposiuin 011 Gastrointestinal Hormones(Vancouver, Canada),J K raicer and GS Marks (eds).Vancouver, pp. 34-35.22. Sundell G and Nilsson G (1986). Structure and func-tion of the dog gastric mucosa during and after a1-year trea tment w ith omeprazo le. 11. Effects on gas-tric acid secretion and blood levels of gastric hor-mones. Scand. J.Gastroenterol. Suppl. 1 18) 2 1: 82-85.23. Wallmark B, Brandstrom A, and Larsson H (1984).Evidence for acid-induced transformation of ome-prazole into an active inhibitor of (H' + K+)-ATPasewithin th e parietal cell. Biochini. Biophys. Acta 778:24. Wallmark B, Carlsson E, Larsson H, Brandstrom A,and L indberg P (1986). New inhibitors ofgastric acidsecretion: Properties and design of H+,K+-ATPase

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