Burimamide, a specific histamine H2-receptor antagonist, is an effective inhibitor of histamine and pentagastrinstimulated gastric acid secretion in the innervated pig stomach. Pepsin secretion, and acid secretion from denervated gastric pouches, were not significantly depressed by burimamide in the dose used in this study. Atropine inhibited pentagastrin- but not histaminestimulated gastric acid secretion from the innervated and denervated portions of the pig stomach.S. Afr. Med. J., 48, 1985 (1974)

Bank, S

Barbezat, GO

Daniel, M

Terblanche, J

Waterworth, MW

English

AJOL - African Journals Online

28 September 1974 S.A. MEDICAL JOURNAL 1985Effect of Burimamide on Histamine- andPentagastrin-Stimulated Acid and PepsinSecretion in the PigG. O. BARBEZAT, M. W. WATERWORTH, M. DANIEL, S. BANK, J. TERBLANCHESUMMARYBurimamide, a specific histamine H2-receptor antagonist,is an effective inhibitor of histamine and pentagastrin-stimulated gastric acid secretion in the innervated pigstomach. Pepsin secretion, and acid secretion fromdenervated gastric pouches, were not significantly de-pressed by burimamide in the dose used in this study.Atropine inhibited pentagastrin- but not histamine-stimulated gastric acid secretion from the innervatedand denervated portions of the pig stomach.S. Afr. Med. l., 48, 1985 (1974).5er...E126r-HISTAMINE 240 )Jg/kg - hr~MAIN ~ltt~CI CONTROl<>...............0-0--0/" .....STOMACH / -_ //1 l"\URIMAMIDE0/ _ /j "'//1-/coE+:I:er....I!432215 MIN PERIODSBi/~NaCI CONTROLHEIDENHAIN ' \PO"CH j' " "---u..-...~~_" 1BURIMAMIDE°1.2E",0.8O. 4CT....E+:I:124 81~ MI~ PFlllnn~sHE I DENHAI NPOUCH! NaCI CONTROL.o_°-o_o_o~~K/-j--------:;t ,"".,.",~1)-o70er...EFig. 1. Effect of burimamide or control saline on histamine-stimulated acid concentration and output from the mainstomach or Heidenhain pouch.S. BANK, M.B. CH.B., F.R.C.P .. Associate ProfessorJ. TERBLANCHE. CH.~1., F.R.C.S.. F.C.S. (S.A.). ProfessorGastro-intestinal Clinic and Departments of Medicine and Surgery, University of Cape Town and Groote SchuurHospital, Cape TownG. O. BARBEZAT, M.D., F.C.P. (S.A.), Senior SpecialistM. \V. WATER\VORTH, F.R.C.S., Senior RegistrarM. DANIEL, B.SC., Senior Technician*Paper presented in part at the International Symposium on Histamine fu-Receptor Antagonists, held in London on I and 2 October 1973.16S.-A. MEDIESE TYDSKRIF240..ug/kg - hr11NaC I CONTROL198620-E<:><:>:::"" 10Ec:'"c.'"C-O100r-HISTAMINEMAINSTOMACH /v"-... v/v_,v "-...v_'/v /1"-... BURIMAMIDE/.----. "'-.. // .-.HEI DENHAINPOUCHcoEenE101028 September 1974rHISTAMINE 240 AJg/kg - hr~lNaCI CONTROLMAIN STOMACH /n~o c-~/ .o I ,101~/·/\;:=7HE I OENHAI NPOUCHE<:><:> 50""Ev~.~ BUR)MAMIDE. ~l~·~. v---:~v_9__i NaCI CONTROLcoE:;;enE4 8 12B 4 8 12 15 MIN PERIODS15 MIN PERIODSFig. 2. Effect of burimamide or control saline on histamine-stimulated pepsin concentration and output from the maiastomach or Heidenhain pouch.Histamine receptors have been divided into two groups,depending upon whether they are or are not blocked byconventional antihistamines such as mepyramine maleate.These have been termed H, and :a receptors respectively.An antagonist of :a receptors (burimamide) has recentlybeen discovered' and a more potent and less toxic ana-logue, metiamide, was subsequently developed. TheseIL receptor antagonists inhibit gastric acid secretionstimulated by histamine, gastrin, hypoglycaemia and foodin the dog' and by histamine and pentagastrin in man.'In this study the effect of burimamide on histamine-and pentagastrin-stimulated gastric acid and pepsin se-cretion was measured in porcine innervated stomach anddenervated gastric pouches.METHODSCross-bred White-Landrace pigs weighing 15 - 25 kg wereprepared with a gastric fistula and a Heidenhain pouch.Two weeks were allowed between surgery and the firststudy. Animals were fasted for 20 hours before each study.Experiments were not done more frequently than once in48 hours. Six studies were performed in random orderon 5 pigs.After two IS-minute basal collections, gastric secretionwas stimulated by intravenous infusions of either penta-gastrin (8j.Lg/kg-h) or histamine acid phosphate (240j.Lg/kg-h), using a Braun Vnita I infusion pump, for 3hours. The doses of histamine and pentagastrin used inthis study were those previously found to stimulate' maxi-mal secretion from porcine denervated gastric pouches:Pigs receiving histamine were given mepyramine maleateintramuscularly 10 minutes before starting the infusion.Ninety minutes after the start of the infusion of stimulant,either burimamide (5 mg/kg of a solution containing 15mg/ml) or a control 0,15M NaCl solution was injectedintravenously over 60 seconds. Animals showed signs ofrestlessness while the burimamide was being injected.Samples were collected every 15 minutes, the volumemeasured, and the acid titrated with 0,2M NaOH usingan automatic titrator (Radiometer, Copenhagen). Aliquotsfrom successive pooled 30-minute samples were deep-frozen at -20'C and the pepsin content assayed 1 - 4weeks later, according to the method of Berstad.'28 September 1974 S.A. MEDICAL JOURNAL 19871215 MIN PERIODSB 4 8i""".HEIDENHAIN \POUCH't'c/ '0.-0\,1• NaC I CONTROLI "'-- 0.'---...."'--0--"""0. i\ "--..0..........0/1 BUR I M AM I 0E. \. • ~f "'- ----"0-~=~ , I,PENTAGASTRIN oJJ9/kg - hr ~~ +BURIMAMIDE ~MA I N .--.-----~../STOMACH 0 .....0-0_0 ."--..NaCI t 0'-.....ZO~ONTROl 0-0,(I ''O;:::::i---.-I '''/~'O---ai I I i32ooLa0.5c:c:-ECT....ECT....E.-E+::I:124 8IS MIN PERIODSB+NaCI CONTROL~o--..:::::::: /o~ °° ~/""" /0" °It ~ iT 0/.• BU".8.'" .~~I/0HEIDENHAINPOUCHr--- PENTAGASTRIN 8JJ9/kg - hr,l 1BURIMAMIDE lMAINSTOMACH /~. °..-/ °-0_ /"--.0-0// NaCI i -0--0. J~t0/°70o14010er...E=....er...E+xFig. 3. Effect of burimamide or control saline on pentagastrin-stimulated acid concentration and output from the mainstomach or Heidenhain pouch.Studies were repeated in 2 pigs weighing 20 and 25 kg,using atropine (600 J-lg given over 60 seconds) instead ofburimamide. The acid response was measured as before.Insulin tests were performed in 3 of the 5 pigs usedin these studies. Hypoglycaemia induced by soluble insulin(0,5 V/kg as an intravenous bolus) was shown to producean acid response from the main stomach but no responsefrom the Heidenhain pouch. Complete denervation of'the pouches was thus confirmed. The 2 other pigs died(l with pneumonia, 1 of uncertain cause) before theinsulin tests could be performed.Differences in acid or pepsin secretion between thehour before and the hour after the injection of buri-mamide or saline were calculated in each individual test.Differences produced by burimamide were compared withdifferences following saline by using the unpaired Student'sI-test.RESULTSThe effect of burimamide on histamine-stimulated acidand pepsin secretion was as follows:Acid secretion (Fig. 1): Burimamide significantly inhibitedacid concentration (P<0,005) and output (P<0,02) inthe main stomach when compared with saline controls.However, the differences in acid concentration and outputin the Heidenhain pouches w'ere not significant (P>0,5and 0,3 respectively).Pepsin secretion (Fig. 2): Histamine·stimulated pepsinconcentration was unaffected by burimamide in eitherinnervated stomach or Heidenhain pouch. Burimamideproduced a drop in the mean pepsin output from themain stomach, but this was not statistically significant.Pepsin output from the Heidenhain pouch was unalteredby burimamide.Burimamide had the following effects on pentagastrinstimulated secretion:Acid secretion (Fig. 3): There was marked fade inpentagastrin-stimulated gastric acid secretion after I t hoursin both the main stomach and denervated gastric pouches.Burimamide significantly inhibited acid concentration(P<0,02) and output (P<0,02) from the main stomach,but again acid concentration was unaffected and acid1988 S.-A. MEDIESE TYDSKRIF 28 September 197420E<=><=>~ 10'"EcV'>C-o.>n.0r-PENTAGASTRIN 8.ug/kg - hr~MAINSTOMACH 10cE<=>'"=EcV'>c-o.>n.r---PENTAGASTRIN 8JJg/kg - hr~MA INSTOMACH! BURIMAMIDE//:~ ./)at~ CONT'R~~o/ 0~/HEIDENHAINPOUCH\. \\ \__________.1 NaC I CONTR Ol\-----:---~:==:=:r BURIMAMIDE\\. \~"" "Cl CONTROL.~"",I~o~oT--·~~~BURIMAMIDEHEIDENHAINPOUCHo10c'"'"=E.-E1284Bo50100E<=><=>'"E15 MIN PERIODS B 4 8 1215 MIN PERIODSFig. 4. Effect of burimamide or control saline on pentagastrin-stimulated pepsin concentration and output from the mainstomach or Heidenhain pouch.output insignificantly lowered in the denervated pouches(P>O,5).Pepsin secretion (Fig. 4): Pentagastrin-stimulated pepsinconcentration and output in gastric secretions from themain stomach and the Heidenhain pouches were un-affected by burimamide.Atropine produced a marked and prolonged inhibitionof pentagastrin-stimulated acid secretion, both in themain stomach and in Heidenhain pouches (Fig. 5). Hista-mine-stimulated gastric acid secretion was unaffected byatropine in either the main stomach or denervated gastricpouches in both the pigs tested.DISCUSSIONHistamine and pentagastrin-stimulated gastric acid secre-tion has been shown to be reduced by burimamide in theinnervated pig stomach. Burimamide was, however, foundto ,be ineffective in reducing acid secretion in denervatedgastric pouches in the doses used in this study. Calculationof the percentage change in acid secretion produced bythe drug or placebo (Fig. 6) emphasises the differencefound between innervated stomach and denervated pouchesin this species. It is not known precisely how H, receptorantagonists reduce acid secretion, although it seems highlyprobable that they block histamine H, receptor sites.If this inhibition is competitive in type, reducing the largedose of stimulant used in this study or increasing theamount of antagonist might produce a different res'I1tin the Heidenhain pouch. It is nevertheless interestingthat the sensitivity of the parietal cells to H, receptorantagonists is altered by denervation. This is compatiblewith the hypothesis proposed by Grossman and Konturek2that histamine, gastrin and acetylcholine each have areceptor site on the parietal cell and that these sitesinteract with one another. The controversy as to whetherhistamine is the final common pathway for stimulationof gastric acid secretion remains unanswered. The obser-vation that burimamide did not significantly reduce acidsecretion in denervated pouches in the pig may findpractical application in that it is not known whetherhumans would react in the same way. Standard doses of28 September 1974 S.A. MEDICAL JOURNAL 1989+I1601208040HISTAMINE 240.ug/kg-hr"'--PENTAGASTRIN 8 .ug/kg-hr----..MAINSTOMACH lATROP'NE..-_ ..,/;~~/<>---/0Hi sIPgcEHISTAMINE 240 JJg/kg-hrOR.----PENTAGASTRIN 8 JJg/kg-hr--.MA IN· ~./\~.STOMACH//I,Ii0'-'----r~l ATROPINE--.-~(V\ ~."'"..........;-- ...--" Pg8 12HEIOENHAINPOUCHO. 51.52.01.0+:J::His! ~E121ATROP INE8PERIODS4MIN15HE I DENHAI NPOUCHr~~• ~Pgo40 I80120160415 MIN PERIODSFig. 5. Effect of atropine on histamine- or pentagastrin-stimulated acid concentration and output from the main stomachor Heidenhain pouch.%aw& III STMlATBJ GASTRIC SECIIETJONC =COO-TIl(lo. {.....ellFig. 6. Percentage change in volume output, acid concen-tration and acid output between the hour before and thehour after burimamide or control saline injections.this drug may therefore be ineffective in patients witha partially or completely denervated stomach.As expected, histamine and pentagastrin did not increasepepsin concentration in the gastric juice. Heidenhain pouchjuice, in fact, initially had a high pepsin concentrationwhich rapidly declined with stimulation, an observationmade previously in the dog.' It was noted that most ofthe samples collected from the gastric fistulae were bile-stained, and it was thought that this might interferequantitatively with pepsin estimation. The colour index ofthese samples was measured (modified from the methoddescribed by Henry et al.,' and no significant negativecorrelation was found between the amount of bile dis-coloration and pepsin concentration (I' = -0,0568 in166 comparisons). Histamine-stimulated pepsin outputfrom the main ·stomach was considerably reduced afterthe burimamide injection, but this was not statisticallysignificant when compared with controls. The vagus andsecretin are strong stimulators of pepsin secretion.'·- Itwould be of interest to note the effect of H, receptorantagonists on pepsin secretion stimulated by neural andhormonal pathways.The effect of atropine on gastric acid secretion differedfrom that of burimamide in that pentagastrin-stimulatedsecretion was markedly depressed in both the mainstomach and the denervated pouches, while histamine-stimulated secretion was unaltered. These results canonly be taken as qualitative, since the numbers studied weresmall. The failure to depress histamine-stimulated acidsecretion may be a resuit of the large dose of stimulant1990 S.-A. MEDIESE TYDSKRIF 28 September 1974used, inhibition of histamine effect by atropine being ofthe competitive type.'·Studies are being conducted with If, receptor blockersin patients with peptic ulceration. Initial results haveindicated that metiamide is associated with a significantreduction of gastric acid secretion, and symptomatic reliefof ulcer dyspepsia. Prolonged double-blind trials arebeing conducted to accurately assess its clinical value.This study was supported by the South African MedicalResearch Council.We wish to thank Smith, Kline & French (Pty) Ltd forsupplies of burimamide.Books ReceivedAids to Postgraduate Medicine. 2nd ed. By J. L. Burton, M.D.,B.sc., M.R.C.P. Pp. vii + 136. £1,25. Edinburgh andLondon: Churchill Livingstone. 1974.Bonney's Gynaecological Surgery. 8th ed. By J. Howkins,M.D., M.S. (Lond.), FR.C.S. (Eng.), FR.C.O.G. and SirJohn Stallworthy, MA, F.R.C.S. (Eng.), Hon. FA.C.S.,Hon. F.C.O.G. (S.A.). Pp. x + 868. Illustrated. £11,00.London: Bailliere TindaI!. 1974.Operating Theatre Technique. 3rd ed. By R. J. Brigden, S.R.N.Pp. 698. Illustrated. £12,50. Edinburgh and London:Churchill Livingstone. 1974.Principles of Bone X-Ray Diagnosis. 3rd ed. ny G. Simon,M.D., F.R.C.P., F.F.R. Pp. xix + 232. Illustrated. RI9,60.London and Durban: Butterworths. 1974.REFERENCES!. Black, J. W., Duncan, W. A. M., Durant~ C. J., Ganellin, C. R.and Parsons, E. M. (1972): Nature (Lond.), 236, 385.2. Grossman, M. I. and Konturek, S. J. (1974): Gastroenterology, (inpress).3. Wyllie, J. H., Hesselbo, T. and Black, 1. W. (1972): Lancet, 2,1117.4. Aroot, R. S. (1973): Unpublished data.5. Berstad, A. (1970): Scand. J. Gastroent., 5, 343.6. Schofield, B., (1957): Gastroenterology, 33, 714.7. Henry, R. J., Golub, O. J., Berkman, S. and Segalove, M. (1953):Amer. J. Clin. Path., 23, 84!.8. Passaro, E, P. jun. and Grossman, M. 1. (1964): Amer. J. Physiol.,206, 1068.9. Stening, G. F., Johnson, L. R. and Grossman, M. I. (1969):Gastroenterology, 56, 468.10. Hirschowitz, B. I., Hutchison, G. and Sachs, G. (1972): Amer. 1.Physiol., 222, 1316.Boeke OntvangA Paediatric Vade-Mecum. 8th ed. Ed, by Ben Wood, D.M.,FR.C.P, Pp. xiii + 190. £2,00. London: Lloyd-Luke.1974.Circulation. Vo!. XLIX, No. 5, Supplement No. I. SurgicalTreatment of Hyperlipidemia. By H. Buchwald, M.D.,Ph.D., R. B. Moore, M.D. and R. L. Varco, M.D., Ph.D.Pp. 37. Illustrated. $1,00. New York: American HeartAssociation. 1974.Occupational Lung Disorders. By W. Raymond Parkes, M.D.,M.R.C.P., D.I.H. Pp. xv + 528. Illustrated. R30,00.London and Durban: Butterworths. 1974.A Primer of Neurology. By J. B. Lyons, M.D., F.R.C.P.I.Pp. vii + 156. R3,80. London and Durban: Butterworths.1974.

Effect of burimamide on histamine- and pentagastrin-stimulated acid and pepsin secretion in the pig

https://www.ajol.info/index.php/samj/article/download/169691/159142

Effect of burimamide on histamine- and pentagastrin-stimulated acid and pepsin secretion in the pig

Abstract

Similar works

Full text

Available Versions

AJOL - African Journals Online