Control Of Gastric Acid Secretion Research Articles

Effects of Omeprazole and Cimetidine on Mucosal Acid Secretion, Blood Flow and Oxygen Consumption in the DogEx VivoGastric Chamber

The three classical receptors associated with control of gastric acid secretion (acetylcholine, gastrin and histamine-H2) influence other cell types beside the parietal cells within the mucosal layer. Agents that inhibit parietal cell secretion, such as adrenergic hormones and prostaglandins, are also known to influence other cells in the mucosa, particularly the microvessels. Omeprazole is a potent inhibitor of gastric acid secretion with no known direct effect on any mucosal cell type other than the parietal cells. This property may enable the direct effects of certain agents on mucosal metabolic activity to be distinguished from the indirect effects resulting from parietal cell inhibition.

The isolated stomach preparation of the mouse: a physiological unit for pharmacological analysis

Although oxyntic cell secretion can be studied at many organisation levels between isolated cell suspensions and non-invasive techniques in animals, the isolated, lumen-perfused, stomach preparation of the mouse represents a hierarchical level which eliminates extrinsic regulatory influences but retains all the cellular architecture known to be necessary for physiological responses and so can be defined as the physiological unit of acid secretion. The feeding pattern before and the distending pressure during an experiment have been identified as the main determinants of basal secretion: the combination of an intragastric pressure of 12 cmH2O and the fasted state generated a stable basal secretion over 2 h providing a satisfactory basis for bioassays. Basal acid secretion was lowered by treatment with omeprazole and sodium thiocyanate but not with tetrodotoxin, N-methylatropine or tiotidine, suggesting that basal secretion does not involve nervous stimulation or the local release of histamine under these experimental conditions. The improved assay permitted the full characterization of cumulative agonist concentration-effect curves in single stomach preparations to histamine, 5-methylfurmethide, pentagastrin and isobutyl-methylxanthine. Interestingly, pentagastrin produced sustained stimulation of gastric acid secretion under conditions when there was no pharmacological evidence that histamine secretion was taking place. This finding is discussed in relation to the role of histamine in the control of gastric acid secretion.

Muscarinic receptors in isolated gastric fundic mucosal cells binding-activity relationships

Muscarinic receptors are involved in the control of gastric acid secretion. The characteristics of ( 3 H)-N- methyl- scopolamine [( 3H)-NMS] binding to isolated cells from rabbit fundic gastric mucosa and inhibition of this binding by muscarinic agonists, antagonists and other pharmacological agents known to regulate acid secretion are reported. Specific binding for ( 3H)-NMS was described: antagonists interact with high affinity sites ( K D = 0.5 nM) whereas binding curves for agonists clearly deviated from the simple mass action isotherm with a flattening of the curve suggesting the presence of more than one class of sites. The low affinity sites for agonists are in the micromolar range. Pirenzine, a gastroselective antimuscarinic compound, known to differentiate between M1 and M2 sites, inhibited ( 3H)-NMS binding with an IC 50 of 0.05 μM. On the same gastric cell population, muscarinic agonist carbachol stimulated ( 14C)-aminopyrine accumulation in a dose-dependent manner with an ED-50 of 10 μM, value close to that needed to 50% inhibit ( 3H)-NMS binding. This stimulation was competitively inhibited by muscarinic antagonists and pA 2-values for atropine, QNB and pirenzepine, calculated from linear Schild plots, were in the following order: 9.2 for atropine, 8.6 for QNB and 7.0 for pirenzepine. In conclusion, fundic gastric mucosal cells from rabbit, isolated with collagenase and EDTA, contained specific muscarinic receptors coupled to the acid secretory mechanism and pirenzepine interact with these receptors with an intermediate affinity suggesting the presence of functional M2-sites.

Endogenous sugar acid control of hypothalamic neuron activity and gastric acid secretion in rats

The feeding related endogenous sugar acids, 2-deoxytetronic acid, 2-DTA and 3-deoxypentonic acid, 3-DPA, were investigated for their peripheral and central (hypothalamic) control of gastric acid secretion, and effects on activity of lateral hypothalamic (LHA) neurons in rats. Peripheral gastric acid secretion was not affected by either 2-DTA or 3-DPA. Slight gastric acid secretion was elicited by 3-DPA only when it was applied directly into the gastric related site of the LHA. Gastric acid secretion induced by 2-deoxy-D-glucose (2DG) was suppressed by application of 2-DTA in the LHA. 3-DPA had no effect on 2DG induced secretion. Electrophoretic application of 2-DTA significantly inhibited the activity of both gastric and non-gastric type glucose-sensitive neurons in the LHA, and 3-DPA significantly excited both types of glucose-sensitive neurons. The results agree with previous reports that 2-DTA and 3-DPA are endogenous satiety and hunger factors, respectively, and act by modulating hypothalamic control of gastric acid secretion which is mediated through gastric type and non-gastric type glucose-sensitive neurons.

Effect of different denervation procedures on catecholamines in the gut.

Sympathectomy has been used to study the role of the sympathetic nervous system in the control of gastric acid secretion. Conflicting results may reflect differences in the sympathectomy procedures used. In a previous study we showed a reduction of catecholamines by more than 90% in the gut wall of the rat after surgical upper abdominal sympathectomy. The aim of the present investigation was to ascertain whether chemical sympathectomy was equally effective and whether total denervation, including combined chemical and surgical sympathectomy together with bilateral truncal vagotomy, would lower the catecholamine levels further. The results showed that chemical sympathectomy reduced noradrenaline levels in fundus (oxyntic) and antrum mucosa to levels similar to those after surgical sympathectomy (less than 5%), but the reduction was less pronounced in the muscle layer of the fundus and antrum and in the pancreas and spleen. Combined surgical and chemical sympathectomy did not reduce noradrenaline more effectively than surgical sympathectomy alone. Vagotomy reduced catecholamines in the stomach by about 50%; in extragastric tissues vagotomy was without effect. Total denervation, including combined surgical and chemical sympathectomy plus vagotomy, did not reduce noradrenaline levels more than surgical sympathectomy alone, suggesting that the proportion of adrenergic fibers that derive from the vagus is quantitatively insignificant but that the vagus exerts a local control of the sympathetic stores of gastric catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholinergic control of gastric acid secretion.

In the perfused stomach preparation of the anaesthetized rat the cholinergic agonists acetylcholine (ACh) and bethanechol stimulated gastric acid secretion. Both agonists produced similar maximal acid output (70 mumols/15 min) when infused intravenously. However, bethanechol was more potent, eliciting half maximal stimulation at 1.98 mumols/kg/h, while the corresponding dose of ACh was 10.95 mumols/kg/h. Secretory responses to either agonist were antagonized in a dose related fashion by blockade of muscarinic receptors with atropine. In contrast, inhibition of nicotinic receptors with hexamethonium produced a striking potentiation of ACh stimulated secretion whilst the bethanechol elicited secretion remained unaffected. In the presence of full nicotinic receptor blockade the ACh response curve was shifted to the left sixfold, half maximal stimulation being produced at 1.79 mumols/kg/h. Cimetidine partially inhibited the secretory responses elicited by either ACh or bethanechol while blockade of adrenoceptors (alpha and beta) did not affect acid output induced by cholinergic agonists. Secretion elicited by ACh is interpreted as being the composite effect of pro-secretory action and an inhibitory mechanism due to the activation of nicotinic receptors. Hexamethonium, through nicotinic receptor blockade, inhibits the restricting mechanism and thus reveals the full stimulatory action of ACh.

Plasma histamine in pig: effect of food and pentagastrin.

Histamine may have a role in the physiological control of gastric acid secretion. We aimed to detect histamine release into the circulation during food and pentagastrin. Non-parametric statistical analysis was used. Seven pigs bearing iliac artery, iliac vein and portal vein cannulae were given a standard meal. Blood samples were collected at 10-minutes intervals over a period of 2 hours for histamine assay. There were no significant changes in whole blood and plasma histamine concentrations in the iliac arterial or venous blood. In portal venous blood, no significant changes were observed in whole blood histamine, but there were significant increases in plasma histamine 40 minutes after food (basal median: 149.0; range: 50.3-258.6 pmol ml-1; 40 minutes, median 214.9; range: 64.2-319.6 pmol ml-1). Four pigs were given pentagastrin, 6 micrograms kg-1 h-1 i.v. Iliac and portal venous bloods were collected for histamine assay before and 15 minutes after pentagastrin infusion. There were no significant changes in the whole blood histamine concentration in either iliac or portal venous blood. A small increase, mean 5%, of plasma histamine concentration was detected in the iliac venous blood (basal mean 242.9 +/- 21.7 pmol ml-1; stimulated mean 256.9 +/- 39.1 pmol ml-1). A 20% increase in the portal plasma histamine concentration was observed after pentagastrin (basal mean 240.1 +/- 13.2; stimulated mean 288.4 +/- 18.8 pmol ml-1). Both food and pentagastrin increase plasma histamine concentration in the portal vein. Pentagastrin has a greater effect than food.

Inhibition by Central Alpha-2 Adrenergic Mechanism of Thyrotropin-Releasing Hormone-Induced Gastric Acid Secretion in the Rat

Influences of central alpha-2 adrenergic agonists on thyrotropin-releasing hormone (TRH)-stimulated gastric acid secretion were examined in the perfused stomach of anesthetized rats. Clonidine, an alpha-2 adrenergic agonist, given subcutaneously or intracerebroventricularly inhibited the gastric acid secretion stimulated by intracerebroventricular TRH. Intracerebroventricular injection of norepinephrine tended to reduce the acid secretion, while phenylephrine, serotonin and quipazine (serotonin agonist) did not influence the acid secretion. Subcutaneous clonidine enhanced the acid secretion peripherally stimulated by electrical vagus stimulation. The inhibitory effect of clonidine on TRH-induced acid secretion was reversed by yohimbine, an alpha-2 adrenergic antagonist, and phentolamine. In conclusion, the present study suggests that the central alpha-2 adrenergic receptor system participates in the TRH-mediated central nervous system control of gastric acid secretion in anesthetized rats.

Inhibition by central alpha-2 adrenergic mechanism of thyrotropin-releasing hormone-induced gastric acid secretion in the rat.

Influences of central alpha-2 adrenergic agonists on thyrotropin-releasing hormone (TRH)-stimulated gastric acid secretion were examined in the perfused stomach of anesthetized rats. Clonidine, an alpha-2 adrenergic agonist, given subcutaneously or intracerebroventricularly inhibited the gastric acid secretion stimulated by intracerebroventricular TRH. Intracerebroventricular injection of norepinephrine tended to reduce the acid secretion, while phenylephrine, serotonin and quipazine (serotonin agonist) did not influence the acid secretion. Subcutaneous clonidine enhanced the acid secretion peripherally stimulated by electrical vagus stimulation. The inhibitory effect of clonidine on TRH-induced acid secretion was reversed by yohimbine, an alpha-2 adrenergic antagonist, and phentolamine. In conclusion, the present study suggests that the central alpha-2 adrenergic receptor system participates in the TRH-mediated central nervous system control of gastric acid secretion in anesthetized rats.

Reliability of Symptoms in Assessing Control of Gastric Acid Secretion in Patients With Zollinger-Ellison Syndrome

In the present study we explored whether the presence or absence of symptoms could provide a reliable way of assessing the adequacy of control of gastric secretion in patients with Zollinger-Ellison syndrome who were treated medically. Over a 5-yr period, 26 Zollinger-Ellison syndrome patients were entered into a prospective study which examined the presence or absence of symptoms that are associated with gastric hypersecretion, the presence of absence of upper gastrointestinal pathology, and the degree of control of gastric acid secretion. During their last admission, 15 of the 26 patients (58%) were symptomatic, but post-drug gastric acid secretion for the 2 h before the next dose of medication was not significantly different from that in asymptomatic patients. This lack of correlation between the presence or absence of symptoms and post-drug gastric acid secretion was evident for the group as a whole, as well as for 8 to 12 patients who underwent multiple admissions. Of 23 patients who underwent upper gastrointestinal endoscopy of x-ray, or both, on their last admission, 12 had pathology. Post-drug gastric acid secretion was less in patients without pathology than in those with pathology. Furthermore, in patients in whom post-drug gastric acid secretion was less than or equal to 10 mEq/h, the criterion of acceptable control used in this study, pathology did not occur. These findings demonstrate that the presence or absence of symptoms cannot be used to assess the adequacy of medical control of gastric acid secretion in patients with Zollinger-Ellison syndrome. In our opinion, maintenance of post-drug gastric acid secretion less than or equal to 10 mEq/h for the 2 h before the next dose of medication is an acceptable criterion for long-term control of gastric secretion in patients with Zollinger-Ellison syndrome.

Mazindol, a non amphetaminergic appetite depressant, affects neuron activity in and control of gastric acid secretion by lateral and ventromedial hypothalamus

Mazindol (MZD), a non amphetaminergic appetite depressant, was studied for its effects on peripheral and hypothalamic control of gastric acid secretion in rats. Gastric acid secretion induced by direct application of cholinergic agents to parietal oxyntic cells of gastric fundal glands (peripheral) was not affected by MZD. Gastric acid secretion induced by systemic (i.v.) or hypothalamic microinjection of insulin or 2-deoxy-D-glucose (hypothalamic) was markedly inhibited by lateral hypothalamic (LHA) microinjection or i.v. injection of MZD. Electroosmotic application of MZD did not affect non-glucose sensitive neurons, but clearly inhibited both gastric and non gastric types of glucose sensitive cells in the LHA. MZD potently excited glucoreceptor neurons in the ventromedial hypothalamus (VMH). Results suggest that MZD directly inhibits activity of LHA (feeding center) neurons and facilitates neurons in the VMH (satiety center). MZD inhibition of hypothalamic control of gastric acid secretion seems to be a result of integrated effects in the feeding control centers of the hypothalamus, so it might thus be expected to be an effective new treatment for obesity.

6 Ranitidine and Other H2-Receptor Antagonists: Recent Developments

Publisher Summary The first H2-receptor antagonists developed were based on a chemical similarity to histamine. The development of an antagonist, burimamide, allowed the definition of a second class of receptor, the H2-receptors. The main clinical indication for Hz-antagonists has been in the control of gastric acid secretion and the treatment of acid aggravated diseases of the upper gastrointestinal tract, such as duodenal ulcer, gastric ulcer and reflux oesophagitis. The need for an improved H2-receptor antagonist led to take a fresh look at the structural requirements for an action at H2-receptor sites. The chapter discusses the biological test systems suitable for assessing activity at H2-receptor sites. It has been primarily concerned with antagonists, but appropriate test systems for assessing new structures need to be able to respond to both agonists and antagonists. There are three main reasons for measuring activity at H2-receptor sites has been mentioned. The chapter has been primarily concerned with assessing new chemical structures both qualitatively and quantitatively in testing and developing the novel compounds described in this chapter.

Muscimol induces gastric acid secretion after central administration

Intracerebroventricular administration of the GABA agonist, muscimol, resulted in a dose-dependent increase in gastric acid secretion in pylorus ligated rats. The maximum increase in gastric acid secretion occurred in the second hour. The GABA antagonist, bicuculline methiodide, reversed the muscimol effect on gastric acid secretion. Intracerebroventricular administration of D-alanine methionine enkephalin, bombesin and calcitonin significantly suppressed the muscimol-induced gastric acid secretion. The present study suggests that the GABAergic system plays a role in the central control of gastric acid secretion.

Hypothalamic and circulating gastrin in the control of gastric acid secretion

Hypothalamic and circulating gastrin in the control of gastric acid secretion

Investigation of the role of extracellular calcium in the control of acid secretion in the isolated whole stomach of the rat.

1 An isolated stomach preparation from immature rats has been used to study the role of extracellular calcium in the control of gastric acid secretion. Calcium was removed from both the serosal and mucosal solutions either in the absence of a chelating agent or in the presence of EGTA.2 Removal of calcium in the absence of EGTA had no significant effect on basal acid secretion or the acid responses to gastrin and dibutyryl cyclic adenosine 3',5'-monophosphate (db cyclic AMP). Under the same conditions there was a marked potentiation of the acid response to histamine, and a reduction of the acid response to acetylcholine which was readily reversed on restoring calcium to the bathing solutions.3 Removal of calcium in the presence of EGTA caused an inhibition of basal acid secretion and of the acid responses to histamine and db cyclic AMP. In each case this reduction in acid output was readily reversed on bathing the stomachs in normal calcium-containing (2.5 mM Ca(2+)) EGTA-free solutions.4 The inhibition of the acid response to histamine produced by Ca(2+)-free solutions which contained EGTA was not reversed on bathing the stomachs in solutions that contained both EGTA (0.1 mM) and an excess of calcium (2.5 mM).5 The removal of extracellular calcium in the absence of EGTA provided evidence that the secretion of H(+) ions is dependent under some conditions on calcium ions. The possibility cannot be excluded that EGTA itself exerts an inhibitory influence on the process of acid secretion.

Influence of the abdominal vagi and gastric antrum on humoral control of gastric acid secretion

AbstractThe influence of the abdominal vagi (especially the gastric antral branch), the antrum, and the duodenum on humoral control of gastric acid secretion was studied in 9 dogs with Heidenhain pouches (HP). The dogs were divided into 2 groups and subjected to the following sequential operations:Group I: (6 dogs) The first operation was section of the antral branch of the vagus nerve. The second operation was antrectomy with Billroth I gastroduodenostomy. The third operation was transthoracic truncal vagotomy.Group II: (3 dogs) The first operation was antrectomy and Billroth II gastrojejunostomy and the second operation was transthoracic truncal vagotomy. During the control period when the dogs had only an HP, pouch acid secretion and serum gastrin level increased after feeding. After antral vagotomy, both pouch secretion and the serum gastrin level after feeding were significantly lower. The second operation of antrectomy with Billroth I gastroduodenostomy in Group I resulted in a further significant decrease in both pouch acid secretion and serum gastrin level. Similar decreases occurred after the first operation of antrectomy with Billroth II gastrojejunostomy in Group II. In both groups, after the final operation of transthoracic truncal vagotomy, pouch acid secretion tended to increase, while the serum gastrin level increased slightly in Group I but not in Group II. It is concluded that vagal innervation of the antrum plays a role in gastrin release and gastric acid secretion.

The effect of atropine on acid secretion stimulated by acetylcholine, histamine and gastrin in the isolated whole stomach of the rat.

1 An isolated stomach preparation from immature rats has been used to study the effect of atropine on gastric acid secretion. 2 The acid secretory response to acetylcholine was not inhibited by atropine at a concentration of 0.3 micrometer. Concentrations of atropine of 1 to 3 micrometer produced a measurable inhibition of acid secretion, and a concentration of atropine of 10 micrometer caused a complete block of acid secretion which could not be surmounted by high concentrations of acetylcholine. 3 The acid secretory response to histamine was not inhibited by concentrations of atropine of up to 1 mM. 4 Concentrations of atropine of 1 micrometer and 10 micrometer did not inhibit gastrin-stimulated acid secretion, although a significant inhibition of acid output was observed with atropine at concentrations of 0.1 mM and 1 mM. 5 These findings are discussed in relation to the role of cholinergic mechanisms in the control of gastric acid secretion.

THE EFFECT OF METIAMIDE ON ACID SECRETION STIMULATED BY GASTRIN, ACETYLCHOLINE AND DIBUTYRYL CYCLIC ADENOSINE 3′, 5′‐MONOPHOSPHATE IN THE ISOLATED WHOLE STOMACH OF THE RAT

1 An isolated stomach preparation from immature rats is described. The lumen of the stomach was perfused and the hydrogen ion activity of the perfusate recorded continuously. 2 The preparation gave dose-dependent responses to gastrin, acetylcholine and dibutyryl cyclic adenosine 3',5'-monophosphate and these responses were readily reversed on washing out the agonist. 3 The acid secretory response to gastrin was inhibited by metiamide at concentrations of 10(-5) M and 3 X 10(-5)M. 4 The acid secretory responses to acetylcholine and dibutyryl cyclic adenosine 3',5'-monophosphate were not inhibited by concentrations of metiamide up to 10(-3) M. 5 These findings are discussed in relation to the role of histamine in the control of gastric acid secretion.

Current concepts on physiologic control of gastric acid secretion. Clinical applications: Ivey KJ: Am J Med 58: 389–397 1975

Current concepts on physiologic control of gastric acid secretion. Clinical applications: Ivey KJ: Am J Med 58: 389–397 1975

Control of gastric acid secretion by histamine H2-receptor antagonists; a pharmacological dream come true.

Summary: A pharmacological break-through has resulted in the development of an effective inhibitor of histamine stimulated gastric acid secretion. The development of histamine H2-receptor antagonists which inhibit also vagal and pentagastrin stimulated acid secretion support the hypothesis that histamine is the final common mediator of gastric acid secretion. Metiamide, an orally effective inhibitor of acid secretion in man and animal is now ready for carefully controlled clinical trials in the treatment of peptic ulcer. While this drug has no anticholinergic side effects it has shown some toxicity in animals studies, a proportion of which is due to its thiourea side chain. Already, one patient treated with metiamide has developed agranulocytosis which reponded to stopping the drug. In spite of this set-back the outlook for medical control of gastric acid secretion and possibility of peptic ulcer disease has distinctly brightened.