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1.
A theory of gastric acid production and self-protection is formulated mathematically and examined for clinical and experimental correlations, implications, and predictions using analytic and numerical techniques. In our model, gastric acid secretion in the stomach, as represented by an archetypal gastron, consists of two chambers, circulatory and luminal, connected by two different regions of ion exchange. The capillary circulation of the gastric mucosa is arranged in arterial-venous arcades which pass from the gastric glands up to the surface epithelial lining of the lumen; therefore the upstream region of the capillary chamber communicates with oxyntic cells, while the downstream region communicates with epithelial cells. Both cell types abut the gastric lumen. Ion currents across the upstream region are calculated from a steady-state oxyntic cell model with active ion transport, while the downstream ion fluxes are (facilitated) diffusion driven or secondarily active. Water transport is considered iso-osmotic. The steady-state model is solved in closed form for low gastric lumen pH. A wide variety of previously performed static and dynamic experiments on ion and CO2 transport in the gastric lumen and gastric blood supply are for the first time correlated with each other for an (at least) semiquantitative test of current concepts of gastric acid secretion and for the purpose of model verification. Agreement with the data is reported with a few outstanding and instructive exceptions. Model predictions and implications are also discussed. 相似文献
2.
The total active transport of chloride ions across the gastric mucosa can be considered as the sum of two fractions; an acidic one which is equivalent to the acid secreted, and an electromotive one which accounts for the electric energy generated by the gastric mucosa. In the present studies, the relationship between this electromotive chloride transport and acid secretion has been investigated, using specific inhibitors. The rate of electromotive chloride transport was found to be essentially unaffected by changes in the rate of acid secretion, and also by inhibition of acid secretion by thiocyanate. On the other hand, diamox, in combination with histamine, was shown to depress or abolish the gastric electromotive force and to inhibit partially the total chloride transport, while acid was secreted at an almost normal rate. This kind of inhibition is undefined as to its mechanism but seems to be more specific for the gastric chloride transport than any other inhibitor known. It is concluded that acid secretion and electromotive chloride transport involve two different mechanisms, and are not absolutely essential for each other. The present results do not support the view that carbonic anhydrase is essential for acid secretion. They rather suggest an important function of this enzyme in the mechanism of active chloride transport. 相似文献
3.
Coskun T Baumgartner HK Chu S Montrose MH 《American journal of physiology. Gastrointestinal and liver physiology》2002,283(5):G1147-G1155
Gastric secretion of hydrochloric acid requires protons and chloride, yet the mechanisms and regulation of gastric chloride secretion remain unclear. We developed an in vivo technique to simultaneously measure acid/base and chloride secretion into the gastric lumen of anesthetized rats. The cannulated stomach lumen was perfused with weakly pH-buffered chloride-free solution containing a chloride-sensitive fluorophore [5 microM N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE)]. Gastric acid and chloride secretion was detected in gastric effluents by 1) flow-through pH electrode and 2) MQAE fluorescence. Gastric effluent was also collected at 1-min intervals for independent determination of chloride amount by chloridometer. In all conditions, both optical and chemical determinations of chloride report similar amounts of secreted chloride. During luminal perfusion with pH 5 solution, net acid and chloride secretion into the lumen was observed. Pentagastrin stimulated both secretions. In contrast, proton pump inhibition (omeprazole) caused alkalinization of the gastric effluent, but chloride secretion was not diminished. During luminal pH 3 perfusion, net alkali secretion was observed, and chloride secretion at luminal pH 3 was greater than pH 5. When tissue is pretreated with omeprazole at luminal pH 3, the addition of prostaglandin E2 synchronously stimulates both alkali and chloride secretion. Results suggest that both acid and alkali secretions are separately coupled with chloride secretion. 相似文献
4.
Kozo Hayashi Kazuo Yamada Keiji Ohe Akima Miyoshi Takashi Kawasaki 《生物化学与生物物理学报:生物膜》1980,596(3):414-419
The effect of amytal on energy metabolism and acid secretion in an isolated gastric mucosa of the guinea-pig were studied. Determination of adenine nucleotides, creatine phosphate, pyruvate and lactate in the gastric mucosa showed that amytal depressed the levels of ATP, creatine phosphate and energy charge with elevation of the AMP and pyruvate levels. This treatment inhibited concomitantly acid secretion and active chloride transport detected by short circuit current. The addition of menadione with ascorbate to the medium in the presence of amytal partially restored ATP and energy charge levels and also induced a partial recovery of acid secretion and active chloride transport. These results suggest that ATP is a direct energy donor for acid secretion in the gastric mucosa of the guinea-pig. 相似文献
5.
H B Dunford A M Lambeir M A Kashem M Pickard 《Archives of biochemistry and biophysics》1987,252(1):292-302
Spectral-scan results obtained on the millisecond time scale are reported for reactions of chloroperoxidase with peracetic acid and chloride ion in both the presence and the absence of monochlorodimedone. A multimixing experiment is performed in which stoichiometric amounts of chloroperoxidase and peracetic acid are premixed for 0.7 s before the resultant compound I is reacted with chloride ion. The combined results show that the only detectable enzyme intermediate species is compound I (except in very late stages of the reaction), that the disappearance of compound I is accelerated by the presence of chloride ion, and that it is further accelerated if both chloride and monochlorodimedone are present. It is concluded that compound I is an obligate intermediate species in the reaction. Experiments are performed on the reaction of monochlorodimedone with hypochlorous acid in both the presence and the absence of added chloride ion, but in the absence of chloroperoxidase. The presence of chloride ion greatly accelerates the reaction rate apparently by setting off a chlorine chain reaction. This reaction would be important in the enzyme-catalyzed reaction if hypochlorous acid were liberated into the solution. A careful analysis of steady-state kinetic results shows that in the chlorination of monochlorodimedone at least, liberation of free hypochlorous acid is not important in the enzyme-catalyzed pathway. Rather the reaction proceeds from compound I to formation of iron(III)-OCl by chloride ion addition to the ferryl oxygen atom. This obligate intermediate species then chlorinates the substrate. It is well described as enzyme-activated hypochlorous acid, in which replacement of the proton in HOCl by the heme iron ion produces a Cl+ species of great potency. Thus the enzyme controls chlorination of monochlorodimedone rather than unleashing an uncontrolled chain reaction in which it would be rapidly destroyed. 相似文献
6.
1. All dyes appearing in gastric juice after intravenous injection in the dog are characterized by having their chromogen in the electropositive ion under suitable conditions. 2. All dyes eliminated in pancreatic juice ionize with the chromogen electronegative under proper circumstances. 3. The amphoteric characteristics of certain dyestuffs, as well as the changes in charge associated with reversible reduction in others, have been taken into consideration, and the lack of success of previous investigators in finding a common characteristic of dyes secreted by the gastric glands differentiating them from those secreted by the pancreas, has been shown to have been due to failure to take these potentialities of the dyestuffs into account. 4. Several possible hypotheses concerning the mechanism of selectivity to dyestuffs have been considered. Differences in distribution in acid, neutral, and alkaline phases will not account for selective secretion without postulating also specific membrane permeability. It is pointed out that the theory most thoroughly in accord with all the facts observed is based upon the pore concept. To restrain electronegative dyes by polar adsorption, the pores of the membranes of the gastric glands would have to be positively charged. Such pores would constitute an electrostatic filter, restraining from passage all mobile ions of the same charge. The anions, which in plasma are mostly chloride, could pass this barrier into the secretion. In order to have hydrochloric acid formation, anion exchange would have to occur, bicarbonate, lactate, or some other anion from the gland lumen returning to balance chloride entering, leaving the hydrogen ion from the weaker acid in the secretion. This tentative theory can also be seen to fit many of the facts of pancreatic secretion, where electropositive dyes are restrained, and alkali is secreted. 相似文献
7.
Four different groups of subjects were given Histalog, insulin or reserpine or acted as controls. Changes were noted in gastric emptying, acid, chloride, parietal and non-parietal secretions and neutral chloride. Gastric emptying and secretion were measured by the Hunt and Spurrell test meal as modified by us for drug testing.Histalog stimulated gastric secretion but not emptying. Insulin stimulated both secretion and emptying. Reserpine stimulated secretion but it stimulated emptying only in one-half of the subjects.After Histalog and reserpine the rise in hydrogen and chloride secretion was equal, so the neutral chloride did not increase. After insulin the rise of chloride was proportionately greater than the rise of hydrogen, so that neutral chloride was increased. 相似文献
8.
Lucas ML 《Journal of physiology and biochemistry》2008,64(1):69-88
Many forms of diarrhoeal disease, particularly so called “secretory” diarrhoeal disease are thought to arise by the active secretion of chloride ion from the enterocytes, creating an osmotic gradient for fluid movement into the small intestinal lumen. This model implies that normally occurring intestinal secretion is catastrophically enhanced by bacterial enterotoxins. This review advocates that neither normal nor abnormal intestinal secretion from the enterocytes occurs and that no competent proof for chloride secretion exists. Prior to 1970, the physiological evidence failed to support the concept of the formation of intestinal juice as a normal intestinal event. support the concept of the formation of intestinal juice as a normal intestinal event. The concept was later revived to explain the high rate of fluid entry into the lumen after exposure to cholera toxin. Much evidence has been advanced for the chloride secretion hypothesis, the dominant secretory paradigm after 1974, but is the evidence sufficiently compelling for it to be regarded as proving the chloride secretory model? The evidence falls into four categories and a fifth conjectural argument that proposes that an abnormal chloride ion channel in cystic fibrotic sufferers confers a natural selective advantage by preventing diarrhoeal disease. Secretion is putatively demonstrated by 1) showing that mass transfer of fluid is into the lumen (secretion) and not merely a failure to transport out of the lumen (failed absorption). Support is offered by 2) chloride ion flux measurementsin vitro in Ussing chambers and by 3) shortcircuit current measurements that are consistent with and purport to show chloride ion movement into the lumen. In addition, 4) pharmacological agents are identified that affect short-circuit current and these are assumed to be anti-secretory, consistent with the biochemical mechanism for secretion, confirmed wherever possible by mouse knock-out models. Finally, the proxy methods used to study water movement such as elevated short-circuit current measurements show these to be absent in cystic fibrotic patients. The enterocyte secretion hypothesis is challenged here on the basis of an examination of the methods used to show secretion, particularly after exposing the small intestine to heat stable enterotoxin (STa) fromE. coli. STa is thought to be secretory because fluid entry into the lumen is claimed, enhanced isotopic flux of chloride ion towards the lumen occurs, an increase in short-circuit current is found, preventable by various drugs that are deemed likely to be anti-secretory and also because the short-circuit current changes after STa are not seen in cystic fibrotic patients. Using volume recoveryin vivo, STa is found not to be secretory but only anti-absorptive. Hence, other techniques used to show secretion are not fit for that purpose. If STa is identified as secretory and yet no secretion occurs, how reliable is the evidence for other toxins being secretory when these methods are used? This review concludes that chloride ion secretion is unproven. A review of the literature indicates that secretion occurs not because epithelial cells actively pump water but by interdiction of fluid absorption, increased conductivity through tight junctions and an increased hydrostatic driving force through elevated capillary pressure. The exclusive focus on chloride secretion may explain the failure to develop antisecretory drugs over the last three decades. 相似文献
9.
Andreeva IuV 《Rossi?skii fiziologicheski? zhurnal imeni I.M. Sechenova / Rossi?skaia akademiia nauk》2004,90(1):112-120
The investigation into the influence of a three-day starvation on the gastric secretion in dogs with Pavlov pouches stimulated by meat, histamine and pentagastrin, was carried out. A 72-hour starvation did not change the summary volume of the gastric juice, debit of the gastric acid, and quantity of pepsin. At the same time the starvation decreased the average rate of gastric juice secretion, gastric acid and pepsin secretion in response to histamine and decreased the pepsin secretion in response to pentagastrin. In this way re-feeding enhanced the average rate of gastric juice secretion and gastric acid secretion on 3-day and pepsin on 5-day in response to meat. The average rate of gastric juice secretion increased on the 5-day after refeeding in response to histamine and the average rate of gastric juice, gastric acid and pepsin secretion in response to pentagastrin. 相似文献
10.
S.J. Hersey 《Biochimica et Biophysica Acta (BBA)/General Subjects》1977,496(2):359-366
Measurement of ATP and creatine phosphate in isolated frog gastric mucosa showed that amytal depressed the level of both high-energy compounds and inhibited acid secretion. Addition of menadione restored the ATP level to control values and partially restored the creatine phosphate levels but did not support acid secretion. Menadione was found to support that portion of active chloride transport which is not associated with acid output. It is concluded that an amytal-sensitive reaction, presumably mitochondrial coupling site I, is required for acid secretion to occur and that ATP is not a sufficient source of energy for this secretory process. 相似文献
11.
1. The effects of ion substitution and various inhibitors on the transmucosal potential, short circuit current, mucosal resistance and acid secretion of the lizard gastric mucosa, incubated in an Ussing chamber, have been determined. 2. Ion substitution experiments indicate that the serosal potential step consists of a combined C1- and K+ diffusion potential, and that the mucosal potential step is Na+ dependent and behaves primarily as a Na+ diffusion potential. 3. Experiments with ouabain indicate that the major (Na+, K+)-ATPase activity responsible for maintenance of cation gradients is located on the serosal side of the mucosal cells, and that this pump activity is non-electrogenic. 4. Experiments with amiloride indicate that a passive sodium influx on the mucosal side is essential for the maintenance of the transmucosal potential and short circuit current. 5. Acid secretion requires the presence of sodium and chloride on the serosal side and the maintenance of a high intracellular potassium level through the (Na+, K+)-ATPase system. 6. The effects of acetazolamide and thiocyanate are compatible with an involvement of carbonic anhydrase and anion-dependent ATPase in acid secretion. 7. Upon initiation of acid secretion the serosal membrane permeability for chloride increases and that for potassium decreases. 相似文献
12.
M Lafontaine G B Cadière M C Woussen-Colle J De Graef 《Archives internationales de physiologie et de biochimie》1983,91(5):459-463
It is well established that duodenal acidification strongly inhibits gastric acid secretion, gastric emptying rate and gastrin release. These effects are at least partly mediated via hormonal pathways, but it is not known whether they are mediated by the release of one peptide named in the past enterogastrone, or by several peptides acting together. The effects of duodenal acidification on gastric acid secretion and gastrin release can be reproduced by infusion of small doses of secretin and plasma secretin levels increase during duodenal acidification or after a meal. This peptide is thus the most probable candidate as an enterogastrone. It has however never been clearly shown that administration of low doses of secretin do decrease gastric emptying rate as well as acid secretion. Experiments were performed on four dogs with gastric fistulas. A peptone solution was infused into the stomach. The experiments were repeated during infusion of synthetic secretin. Our results indicate that infusion of low doses of secretin reproduce all the effects of duodenal acidification: a significant inhibition of gastric acid secretion, gastrin release and gastric emptying rate. 相似文献
13.
A cytochemical technique for localizing cytochrome oxidase activity, based upon the oxidative polymerization of 3,3-diaminobenzidine (DAB) to an osmiophilic reaction product, has been employed to test the possibility of extramitochondrial cytochrome oxidase in gastric mucosa. Deposition of reaction product was found to be exclusively localized within mitochondris; in particular, no reaction product was observed at the apical plasma membrane. Measurements of the effect of DAB on acid secretion revealed a biphasic action consisting of an initial stimulation followed by inhibition. The stimulation of secretion of DAB is interpreted to indicate that DAB is oxidized via a pathway which is linked to the secretory process. The combined cytochemical and physiological measurements provide evidence that the metabolic energy supply for acid secreation is derived from mitochondrial reactions. The results are discussed in relation to current models for the coupling between acid secreation and oxidative metabolism. 相似文献
14.
Ajibola ES Adeleye OE Okediran BS Rahman SA 《Nigerian journal of physiological sciences》2010,25(1):59-62
The effect of an aqueous leaf extract ofAnacardium occidentale on gastric acid secretion was tested in rats. Twenty (20) Wistar albino rats were used for the gastric acid assay experiment. The rats were divided into 2 groups of 10 each. Gastric acid output was determined by continuous perfusion of rat stomach in urethane anesthetized rats. Control gastric acid output was obtained using 0.9% sodium chloride as perfusate and extract induced gastric acid output was obtained by perfusion with 0.1% solution of Anacardium occidentale Intragastric administration of the extract caused significant increase in mean gastric output (P <0.05). Atropine (5μg/100g,) lM and Cimetidine (5mg/100g), IM. significantly inhibited the extract induced gastric acid secretion via muscarinic and histaminic receptors respectively. Our findings showed that the use of the plant extract as a single anti-gastric ulcer therapy may not involve lowering of acid secretions rather it may be due to its anti Helicobacter pylori effect. 相似文献
15.
Aihara T Nakamura Y Taketo MM Matsui M Okabe S 《American journal of physiology. Gastrointestinal and liver physiology》2005,288(6):G1199-G1207
Muscarinic acetylcholine receptors play an important role in the regulation of gastric acid secretion stimulated by acetylcholine; nonetheless, the precise role of each receptor subtype (M(1)-M(5)) remains unclear. This study examined the involvement of M(1), M(3), and M(5) receptors in cholinergic regulation of acid secretion using muscarinic receptor knockout (KO) mice. Gastric acid secretion was measured in both mice subjected to acute gastric fistula production under urethane anesthesia and conscious mice that had previously undergone pylorus ligation. M(3) KO mice exhibited impaired gastric acid secretion in response to carbachol. Unexpectedly, M(1) KO mice exhibited normal intragastric pH, serum gastrin and mucosal histamine levels, and gastric acid secretion stimulated by carbachol, histamine, and gastrin. Pirenzepine, known as an M(1)-receptor antagonist, inhibited carbachol-stimulated gastric acid secretion in a dose-dependent manner in M(1) KO mice as well as in wild-type (WT) mice, suggesting that the inhibitory effect of pirenzepine on gastric acid secretion is independent of M(1)-receptor antagonism. Notably, M(5) KO mice exhibited both significantly lower carbachol-stimulated gastric acid secretion and histamine-secretory responses to carbachol compared with WT mice. RT-PCR analysis revealed M(5)-mRNA expression in the stomach, but not in either the fundic or antral mucosa. Consequently, cholinergic stimulation of gastric acid secretion is clearly mediated by M(3) (on parietal cells) and M(5) receptors (conceivably in the submucosal plexus), but not M(1) receptors. 相似文献
16.
C Prinz M Kajimura D Scott H Helander J Shin M Besancon K Bamberg S Hersey G Sachs 《The Yale journal of biology and medicine》1992,65(6):577-596
The regulation of acid secretion was clarified by the development of H2-receptor antagonists in the 1970s. It appears that gastrin and acetylcholine exert their effects on acid secretion mainly by stimulation of histamine release from the enterochromaffin-like (ECL) cell of the fundic gastric mucosa. The isolated ECL cell of rat gastric mucosa responds to gastrin/cholecystokinin (CCK), acetylcholine, and epinephrine with histamine release and to somatostatin and R-alpha-methyl histamine by inhibition of histamine release. Histamine and acetylcholine stimulate the parietal cell by elevation of cAMP or [Ca]i by activation of H2 or M3 receptors, respectively. These independent pathways converge to activate the gastric acid pump, the H+,K+ ATPase. Activation is a function of the association of the ATPase with a potassium chloride transport pathway that occurs in the membrane of the secretory canaliculus of the parietal cell. Hence the secretory canaliculus is the site of acid secretion, the acid being pumped into the lumen of the canaliculus. The pump is composed of two subunits, a large catalytic and a smaller glycosylated protein. This final step of acid secretion has become the target of drugs also designed to inhibit acid secretion. The target domain of the benzimidazole class of acid pump inhibitors is the extracytoplasmic domain of the pump that is secreting acid, and the target amino acids are the cysteines present in this domain. The secondary structure of the pump can be analyzed by determining trypsin-sensitive bonds in intact, cytoplasmic-side-out vesicles of the ATPase, and it has been shown that the alpha subunit has at least eight membrane-spanning segments. Omeprazole, the first acid pump inhibitor, forms a disulfide bond with cysteines in the extracytoplasmic loop between the fifth and sixth membrane-spanning segment and to a cysteine in the extracytoplasmic loop between the seventh and eight segments, preventing phosphorylation of the pump by ATP. As a result of the effective and long-lasting inhibition of acid secretion by the acid pump inhibitor, superior clinical results have been found in all forms of acid-related disease. 相似文献
17.
Gas phase ethyl acetate production was studied using a porcine pancreatic lipase powder. It was observed that gaseous ethyl acetate was produced from gaseous ethanol and acetic acid. Accordingly, the effects of amount of lipase powder, gaseous ethanol and acetic acid concentrations, and reaction temperature on the performance of a batch bioreactor were investigated. Apparent Michaelis-Menten constant of ethanol was 0.163 [μM] and there was no inhibition by ethanol over the range investigated. As acetic acid concentration increased, ethyl acetate production increased to a maximum, then decreased, thus suggesting the inhibition effects by acetic acid. Over the reaction temperature of 25–55?°C, activation energy was calculated as 3.93 kcal/gmol and initial reaction rate was obtained as follows: r?=?75.7 exp(?1975.7/T) [μM/mg of lipase/hr] 相似文献
18.
Hagen SJ Wu H Morrison SW 《American journal of physiology. Gastrointestinal and liver physiology》2000,279(2):G400-G410
This study was undertaken to determine the mechanism by which ammonium chloride (NH(4)Cl) inhibits stimulated acid secretion in the bullfrog gastric mucosa. To this end, four possible pathways of inhibition were studied: 1) blockade of basolateral K(+) channel, 2) blockade of ion transport activity, 3) neutralization of secreted H(+) in the luminal solution, or 4) ATP depletion. Addition of nutrient 10 mM NH(4)Cl (calculated NH(3) concentration = 92.5 microM and NH(4)(+) concentration = 9.91 mM) inhibited acid secretion within 30 min. Inhibition of acid secretion did not occur by blockade of basolateral K(+) channel activity or ion transport activity or by neutralization of the luminal solution. Although ATP depletion occurred in the presence of NH(4)Cl, the magnitude of ATP depletion in 30 min was not sufficient to inhibit stimulated acid secretion. By comparing the effect of NH(4)Cl on the resistance of inhibited or stimulated tissues, we demonstrate that NH(4)Cl acts specifically on stimulated tissues. We propose that NH(4)Cl blocks activity of an apical K(+) channel present in stimulated oxyntic cells. Our data suggest that the activity of this channel is important for the regulation of acid secretion in bullfrog oxyntic cells. 相似文献
19.
McDaniel N Pace AJ Spiegel S Engelhardt R Koller BH Seidler U Lytle C 《American journal of physiology. Gastrointestinal and liver physiology》2005,289(3):G550-G560
Na-K-2Cl cotransporter-1 (NKCC) has been detected at exceptionally high levels in the gastric mucosa of several species, prompting speculation that it plays important roles in gastric secretion. To investigate this possibility, we 1) immunolocalized NKCC protein in the mouse gastric mucosa, 2) compared the volume and composition of gastric fluid from NKCC-deficient mice and their normal littermates, and 3) measured acid secretion and electrogenic ion transport by chambered mouse gastric mucosa. NKCC was localized to the basolateral margin of parietal cells, mucous neck cells, and antral base cells. In NKCC-deficient mice, gastric secretions of Na+, K+, Cl-, fluid, and pepsinogen were markedly impaired, whereas secretion of acid was normal. After stimulation with forskolin or 8-bromo-cAMP, chambered corpus mucosa vigorously secreted acid, and this was accompanied by an increase in transmucosal electrical current. Inhibition of NKCC with bumetanide reduced current to resting levels but had no effect on acid output. Although prominent pathways for basolateral Cl- uptake (NKCC) and apical Cl- exit [cystic fibrosis transmembrane conductance regulator (CFTR)] were found in antral base cells, no impairment in gastric secretion was detected in CFTR-deficient mice. Our results establish that NKCC contributes importantly to secretions of Na+, K+, Cl-, fluid, and pepsinogen by the gastric mucosa through a process that is electrogenic in character and independent of acid secretion. The probable source of the NKCC-dependent nonacidic electrogenic fluid secretion is the parietal cell. The observed dependence of pepsinogen secretion on NKCC supports the concept that a nonacidic secretory stream elaborated from parietal cells facilitates flushing of the proenzyme from the gastric gland lumen. 相似文献
20.
El-Zaatari M Grabowska AM McKenzie AJ Powe DG Scotting PJ Watson SA 《Regulatory peptides》2008,146(1-3):131-139
The Shh pathway has been implicated in gastric carcinogenesis, and inhibition of this pathway has been shown to inhibit tumour growth in gastric cell lines. Assessing the in vivo efficacy of Shh pathway antagonists in blocking Shh signaling in the stomach is important for clinical trial design, but has not been previously investigated. We investigated the in vivo efficacy of a Shh antagonist, cyclopamine, in correlation to the secondary effects induced by this treatment on gastrin levels and acid secretion. Gastrin has been shown to induce Shh production, processing and activity, which is believed to be mediated by acid secretion. We tested this hypothesis and showed that hypergastrinaemia induces Shh production in vivo, and confirmed that this effect on Shh is mediated by acid secretion. We showed that cyclopamine treatment induces both hypergastrinaemia and Shh, and does not inhibit Gli-1. Inhibition of the effect of hypergastrinaemia on the Shh pathway, in cyclopamine-treated mice, was demonstrated by use of lansoprazole which concomitantly inhibited Gli-1, and did not increase Shh production. Therefore, this evidence suggests that hypergastrinaemia, via increased acid secretion, may increase expression of Shh and that Shh antagonists may require concomitant acid inhibition to successfully inhibit a pathway known to be up-regulated in gastric carcinogenesis. 相似文献