Effects of 16,16=dirnethylprostaglandin E, on bile-induced histamine release and permeability alterations in canine oxyntic mucosal
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Department o f Physiology, University o f Western Ontario, London, Ont., Canada NBA 5Cl Received July 10, 1978 TEPPERMAN, B. L. 1979. Effects of 16,16-dimethyl prostaglandin Ez on bile-induced histamine release and permeability alterations in canine oxyntic musosa. Can. J. Physiol. Pharmacal. 57, 25 1-256. Damage to the stomach results in excessive movement of hydrogen ion (H') out of the lumen, and increased movement of sodium (Na') and potassium (K') into the lumen. Histamine liberation during damage probably adds to the destruction by increased capillary permeability and formation of edema. Previous reports have shown tltat the synthetic prostaglandin analogue 16,16-dimethyl prostaglandin Es (dm PGE,) protects dog gastric mucosa from aspirin- and ethanol-induced gastric mucosal damage. The effects of dm PGEa on bile salt (sodium taurocholate) induced injury has not been investigated. Using the canine Heidenhaill pouch, the present study examined the action of dm PGE2 on gastric mucosal damage induced by 5 m h l sodium taurocholate in 100 mhf MCI. Bile salt damaged the pouch nlucosa as evidenced by an increased loss of H', and increased net fluxes of both Na' and K'. There was also an increase in the histamine content of the fluid irrigating tlne Heidenhain pouch. Intravenous injection of dm PGE2 in the doses 0.1 and 1.0 pg/kg $ h before administration of the sodium taurocholate in HC1 significantly reduced the net lass of H + and the gain of N a t , K', and histamine. It is concluded the dm PGEs effectively protects the canine gastric mucosa from the damaging eRects of bile salt and that the mechanism of dm PGEa protection of canine oxyntic mucosa may be mediated in part via inhibition of the gastric mucosal release of histamine. TEPPERMAN, B. L. 1979. Effects of 16,16-dhethyl prostaglandin E2 on bile-induced histamine release and permeability alterations in canine oxyntic musosa. Can. 9. Physiol. Pharmacsl. 57, 25 1-256. Un dommage de l'estomac risulte en une sortie excessive d'ions hydrogtne (H') de la lumiere, aiilsi qu'cn Line augmentation de l'entree de sodium (Na-) et de potassium (K') vers la lumi6re. La libtration d'histamine durant les dommages contribue probablement ii la destruction par un accroissement de la permtabilit6 capillaire et la formation d'un oedtmc. Bes rapports anttrieurs ont montrt que l'analogue synthttique de la prostaglandine, le 16,16-dimethyl prostaglandine Es (dm PGE2), prottge la muqueuse gastrique du chien des dommages causCs par l'aspirine et l'tthanol. Les effets du dm PGE, sur les dommages causes par les scls biliaires (taurocholate de sodium) n'ont pas btt Ctudits. On utilise dans cette etude la poche de Heidenhain du cbien pour examiner l'action du P S E 2 sur les dommages causts B la muqueuse gastrique par du taurocholate de sodium 5 mM dans 100 mM HC1. Les sels biliaires endommagent la muqueuse de la poche ainsi que le prauve une plus grande perte de H ' , des flux nets de Na' et de K+ qui sont augmentts. On a aussi une augmentation du contenu en histamine du fluide irriguant la poche de Heidenhain. Des injections intraveineuses de dm PGEa B des doses de 0.1 et 1.0 ,ug/kg, k h avant l'administration de taurocholate de sodium dans le HCl, rtduisent de fason ~ n a r q u i ela perte nette de H' et le gain de N a t , de K' et d'histamine. Ow en conclut que le dm PGE, protZge efficacement la nluqucuse gastrique du chien des effets dommageables des sels biliaires et que le mecanisme de protection de la muqueuse oxyntique du chien par le dm PGEp pourrait 6tre partiellement contrdlte par une inhibition de la libiration d'histamine par la muqueuse gastrique. [Traduit par le journal]
Introduction The oxyntic gland area of the stomach contaills a barrier to H'. Na+, and K+ diffusion. ~ fhowever, , ABHR~~VIATION: dm PGE,, 16,16-dimethyl prostaglandin E
L.).
'Medical Research Council of Canada, grant No. MA6426.
the barrier is damaged by topical application of ulcerogenic agents9H+ moves out of the lumen of the ston~achtoward the serosal side and the NaC flux increases in the opposite direction (Davenport 1964, 1965, 1967) , addition, cells are disrupted ruld K+ moves i n p the fluid bathing the mucosa* In the (Johnson and Overholt 1967) and rat (Johnson
0008-42 12/79/03025 1-06$01.00/0 @ 1979 National Research Council of Canada/Conseil national de recherches du Canada
252
CAN. J. PHYSHOL. PHARMACBL. VOL. 5'7, 19'79
1966) darnage results in the release of gastric mucssal histamine and the appearance of histamine in the gastric juice (Joia~~son and O ~ ~ e r h o 1967) lt let has been postulated that histamine is released and is in part responsible for the ensuing gastric erosions by causing fluid productio~a,inacreased mucosal peraneability, and edema. Recently it has been dcmonstratect in the rat that the incidence of gastric lesions associated with mucosal damage carass$ by topically applied aspirin, ethanol, or bile can be reduced or abolished by various natural or synthetic prostaglandins (Carmichael et cel. 19777;Ferguson et id.1973; Main aand LVhittle 1975; ,Vanan B 9'76; Robert 19'76; Robert et aH, 1976; Robert et al. 1977). Furtlaermore, in preliminary communications Miller and Tepperman ( I 977) and Tepperman el a / . (19'78) have reported that in the dog the synthetic prostaglandin analogue dm PGE2 reduced the disappearance of H" aand the appearance of both Naf and K+ associated with aspirin- and ethanol-induced gastric mucosal damage. The purpose of the present study was to assess the protective effects of dm PGE2 against the damaging action of bile salt (sodium taurocholate) on canine gastric nrucosa in terms of alterations is? the ionic integrity of the gastric mucosa. Ftrrthermore, the possibility Baas been investigated that the protective effect of dm PGE? might i ~ spart be mediated via a reduction in mucosal histamine liberation.
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIV CHICAGO on 12/25/14 For personal use only.
).
m.%g HCl. A final hour of colIections (periods 9-12) with the control sc~lutionended the experiment. r of experi~nentsthc effects of two doses In a ~ ~ o t h eseries 60.1 and 1.0 ug/kg) of dm PGE2o n the changes induced by 5 mL44 sodialnn taurocholate were assessed. The dnn PGE, was provided as a gift from the Upjshn Company by Dr. John Pike. The design of these experiments was similar to those described aboa~eexcept that, after the control period, dm PGE- was injected intravenolasly as a single bolaas in the appropriate tcst dose, following which the control period was extended for an additional 330 mine Following each 15-man collection, the volume avm mmeasw e d and the acid concentrationa determined by titration to pH 7.0 witfa 0.2 1%' NaOH using an Autoburette and p H meter (Radiometer Copenhagen). The Na+ &and K' concentration of each sample was determined by flame phc~tometry (IE wnodel 143). Total arnclaants of Wa*, K t ,and H' in the recovered fluid vblere calculated for each period. The net ffrm of each ion waq determined by subtractil-sg the amount put into the pouch from the amount recovered and expressed as miiroequivalernts per 15 min. The histamine content of the fluid drained from the Heicienhain pouch was n-aeasa~redflrasroscopica?ly by the nsethod of Shore et ol. (1959) lasing an Aminco-Bowman Spectropholofluoro~neter (American Instruments Co. Ins., Silver Springs, Maryland). Fluorescence was also measlared in the standard acid and taurocholate acid solutions not exposed to the mucosa and these blank readings were subtracted from the values sbtairled from solrations drained from the pouch. The histamine content was determined and expressed its ~a:momoles. Experiments were done on each dog no more than twice a week. All the results are expressed as means and qtandard error3 of the means. Control values in each experiment were obtained by averaging the final two 15-min periods s f the initial control period. T h e effects of bile salt and dm P G E were compared lasing the I-test for either unpaired or paired 0.05. data. Differences were considered significant when p
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIV CHICAGO on 12/25/14 For personal use only.
Department o f Physiology, University o f Western Ontario, London, Ont., Canada NBA 5Cl Received July 10, 1978 TEPPERMAN, B. L. 1979. Effects of 16,16-dimethyl prostaglandin Ez on bile-induced histamine release and permeability alterations in canine oxyntic musosa. Can. J. Physiol. Pharmacal. 57, 25 1-256. Damage to the stomach results in excessive movement of hydrogen ion (H') out of the lumen, and increased movement of sodium (Na') and potassium (K') into the lumen. Histamine liberation during damage probably adds to the destruction by increased capillary permeability and formation of edema. Previous reports have shown tltat the synthetic prostaglandin analogue 16,16-dimethyl prostaglandin Es (dm PGE,) protects dog gastric mucosa from aspirin- and ethanol-induced gastric mucosal damage. The effects of dm PGEa on bile salt (sodium taurocholate) induced injury has not been investigated. Using the canine Heidenhaill pouch, the present study examined the action of dm PGE2 on gastric mucosal damage induced by 5 m h l sodium taurocholate in 100 mhf MCI. Bile salt damaged the pouch nlucosa as evidenced by an increased loss of H', and increased net fluxes of both Na' and K'. There was also an increase in the histamine content of the fluid irrigating tlne Heidenhain pouch. Intravenous injection of dm PGE2 in the doses 0.1 and 1.0 pg/kg $ h before administration of the sodium taurocholate in HC1 significantly reduced the net lass of H + and the gain of N a t , K', and histamine. It is concluded the dm PGEs effectively protects the canine gastric mucosa from the damaging eRects of bile salt and that the mechanism of dm PGEa protection of canine oxyntic mucosa may be mediated in part via inhibition of the gastric mucosal release of histamine. TEPPERMAN, B. L. 1979. Effects of 16,16-dhethyl prostaglandin E2 on bile-induced histamine release and permeability alterations in canine oxyntic musosa. Can. 9. Physiol. Pharmacsl. 57, 25 1-256. Un dommage de l'estomac risulte en une sortie excessive d'ions hydrogtne (H') de la lumiere, aiilsi qu'cn Line augmentation de l'entree de sodium (Na-) et de potassium (K') vers la lumi6re. La libtration d'histamine durant les dommages contribue probablement ii la destruction par un accroissement de la permtabilit6 capillaire et la formation d'un oedtmc. Bes rapports anttrieurs ont montrt que l'analogue synthttique de la prostaglandine, le 16,16-dimethyl prostaglandine Es (dm PGE2), prottge la muqueuse gastrique du chien des dommages causCs par l'aspirine et l'tthanol. Les effets du dm PGE, sur les dommages causes par les scls biliaires (taurocholate de sodium) n'ont pas btt Ctudits. On utilise dans cette etude la poche de Heidenhain du cbien pour examiner l'action du P S E 2 sur les dommages causts B la muqueuse gastrique par du taurocholate de sodium 5 mM dans 100 mM HC1. Les sels biliaires endommagent la muqueuse de la poche ainsi que le prauve une plus grande perte de H ' , des flux nets de Na' et de K+ qui sont augmentts. On a aussi une augmentation du contenu en histamine du fluide irriguant la poche de Heidenhain. Des injections intraveineuses de dm PGEa B des doses de 0.1 et 1.0 ,ug/kg, k h avant l'administration de taurocholate de sodium dans le HCl, rtduisent de fason ~ n a r q u i ela perte nette de H' et le gain de N a t , de K' et d'histamine. Ow en conclut que le dm PGE, protZge efficacement la nluqucuse gastrique du chien des effets dommageables des sels biliaires et que le mecanisme de protection de la muqueuse oxyntique du chien par le dm PGEp pourrait 6tre partiellement contrdlte par une inhibition de la libiration d'histamine par la muqueuse gastrique. [Traduit par le journal]
Introduction The oxyntic gland area of the stomach contaills a barrier to H'. Na+, and K+ diffusion. ~ fhowever, , ABHR~~VIATION: dm PGE,, 16,16-dimethyl prostaglandin E
L.).
'Medical Research Council of Canada, grant No. MA6426.
the barrier is damaged by topical application of ulcerogenic agents9H+ moves out of the lumen of the ston~achtoward the serosal side and the NaC flux increases in the opposite direction (Davenport 1964, 1965, 1967) , addition, cells are disrupted ruld K+ moves i n p the fluid bathing the mucosa* In the (Johnson and Overholt 1967) and rat (Johnson
0008-42 12/79/03025 1-06$01.00/0 @ 1979 National Research Council of Canada/Conseil national de recherches du Canada
252
CAN. J. PHYSHOL. PHARMACBL. VOL. 5'7, 19'79
1966) darnage results in the release of gastric mucssal histamine and the appearance of histamine in the gastric juice (Joia~~son and O ~ ~ e r h o 1967) lt let has been postulated that histamine is released and is in part responsible for the ensuing gastric erosions by causing fluid productio~a,inacreased mucosal peraneability, and edema. Recently it has been dcmonstratect in the rat that the incidence of gastric lesions associated with mucosal damage carass$ by topically applied aspirin, ethanol, or bile can be reduced or abolished by various natural or synthetic prostaglandins (Carmichael et cel. 19777;Ferguson et id.1973; Main aand LVhittle 1975; ,Vanan B 9'76; Robert 19'76; Robert et aH, 1976; Robert et al. 1977). Furtlaermore, in preliminary communications Miller and Tepperman ( I 977) and Tepperman el a / . (19'78) have reported that in the dog the synthetic prostaglandin analogue dm PGE2 reduced the disappearance of H" aand the appearance of both Naf and K+ associated with aspirin- and ethanol-induced gastric mucosal damage. The purpose of the present study was to assess the protective effects of dm PGE2 against the damaging action of bile salt (sodium taurocholate) on canine gastric nrucosa in terms of alterations is? the ionic integrity of the gastric mucosa. Ftrrthermore, the possibility Baas been investigated that the protective effect of dm PGE? might i ~ spart be mediated via a reduction in mucosal histamine liberation.
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIV CHICAGO on 12/25/14 For personal use only.
).
m.%g HCl. A final hour of colIections (periods 9-12) with the control sc~lutionended the experiment. r of experi~nentsthc effects of two doses In a ~ ~ o t h eseries 60.1 and 1.0 ug/kg) of dm PGE2o n the changes induced by 5 mL44 sodialnn taurocholate were assessed. The dnn PGE, was provided as a gift from the Upjshn Company by Dr. John Pike. The design of these experiments was similar to those described aboa~eexcept that, after the control period, dm PGE- was injected intravenolasly as a single bolaas in the appropriate tcst dose, following which the control period was extended for an additional 330 mine Following each 15-man collection, the volume avm mmeasw e d and the acid concentrationa determined by titration to pH 7.0 witfa 0.2 1%' NaOH using an Autoburette and p H meter (Radiometer Copenhagen). The Na+ &and K' concentration of each sample was determined by flame phc~tometry (IE wnodel 143). Total arnclaants of Wa*, K t ,and H' in the recovered fluid vblere calculated for each period. The net ffrm of each ion waq determined by subtractil-sg the amount put into the pouch from the amount recovered and expressed as miiroequivalernts per 15 min. The histamine content of the fluid drained from the Heicienhain pouch was n-aeasa~redflrasroscopica?ly by the nsethod of Shore et ol. (1959) lasing an Aminco-Bowman Spectropholofluoro~neter (American Instruments Co. Ins., Silver Springs, Maryland). Fluorescence was also measlared in the standard acid and taurocholate acid solutions not exposed to the mucosa and these blank readings were subtracted from the values sbtairled from solrations drained from the pouch. The histamine content was determined and expressed its ~a:momoles. Experiments were done on each dog no more than twice a week. All the results are expressed as means and qtandard error3 of the means. Control values in each experiment were obtained by averaging the final two 15-min periods s f the initial control period. T h e effects of bile salt and dm P G E were compared lasing the I-test for either unpaired or paired 0.05. data. Differences were considered significant when p
