The interaction of choline esters, vagal stimulation and H2-receptor blockade on acid secretion in vitro

doi:10.1016/0014-2999(82)90057-7

European Journal of Pharmacology

Volume 80, Issues 2–3, 21 May 1982, Pages 217-224

https://doi.org/10.1016/0014-2999(82)90057-7 Get rights and content

Abstract

Choline esters, bethanechol and carbachol, and electrical field stimulation increased acid secretion in the mouse, isolated, lumen-perfused, stomach. Electrical field stimulation was apparently mediated by vagal nerve endings because treatment with either tetrodotoxin or atropine abolished the response. Using a 2 + 2 assay design, experiments with bethanechol showed that the H₂-receptor antagonists metiamide and cimetidine (1 mM) were devoid of antimuscarinic activity. However, the effects of carbachol, which unlike bethanechol stimulates both muscarinic and nicotinic receptors, were significantly antagonised by metiamide (1 mM) at a concentration which was not anticholinergic. We conclude that there are cholinergic receptors separate from histamine H₂-receptors on parietal cells. The effects of vagal stimulation in this preparation however, are apparently mediated by histamine release. These results support the ‘two-cell hypothesis’ where vagal nerve endings synapse with the parietal cell.

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Cited by (31)

Analytical pharmacology and the elucidation of function
2011, Trends in Pharmacological Sciences
Citation Excerpt :
We are grateful for the opportunity to pay tribute to James Black's outstanding contributions to pharmacology, physiology and medicine. One of us (J.A.) was privileged to experience at first hand Black's passion for developing biological assays and subjecting them to deep analysis, as illustrated in their work on vagally mediated gastric acid secretion [1]. Crucial for these studies was the discovery of the histamine H2-receptor antagonist drugs, which became the sheet anchor for the treatment of peptic ulcer for over 20 years [2].
James Black believed that analysis of biological assays provides insights into the operation of physiological control systems. In this paper, we illustrate this point in three ‘cardiovascular’ assays. The first determined the half-life (t½) of ‘endothelium-derived relaxing factor’ (EDRF), using bradykinin to release EDRF, which produced concentration-related relaxations of a precontracted artery. With the introduction of time delays between the source of EDRF and the assay artery, there were rightward shifts in dose-response curves, which provided the basis of calculating t½. The second assay determined the roles of noradrenaline reuptake and prejunctional α₂-adrenoceptor activity on transmitter concentration at sympathetic synapses with atria and resistance vessels. In the former, the reuptake role was paramount, whilst prejunctional receptor activity was dominant at vascular synapses, owing to anatomical differences. The third assay provided in vivo estimates of the enhancement of the total peripheral resistance responses to constrictor and dilator stimuli owing to the structural changes in hypertension. Major nonlinearities in the dose-response curve obscured this enhancement. Their effect was avoided by deriving extended dose-response curves from combined constrictor and dilator data, permitting calculation of the enhancement over the range between the nonlinearities.
Gastrin release: Antrum microdialysis reveals a complex neural control
2010, Regulatory Peptides
We used microdialysis to monitor local gastrin release in response to food, acid blockade and acute vagal excitation. For the first time, gastrin release has been monitored continuously in intact conscious rats in a physiologically relevant experimental setting in a fashion that minimizes confounding systemic effects. Microdialysis probes were placed in the submucosa on either side of the antrum, 3 days before the experiments. The concentration of gastrin in the antral submucosal compartment was about 20 times higher than in the microdialysate and estimated to be 5–10 times higher than in serum regardless of the prandial state. The rats were conscious during microdialysis except when subjected to electrical vagal stimulation. Acid blockade (omeprazole treatment of freely fed rats for 4 days), or bilateral sectioning of the abdominal vagal trunks (fasted, 3 days post-op.), raised the gastrin concentration in blood as well as microdialysate. The high gastrin concentration following omeprazole treatment was not affected by vagotomy. Vagal excitation stimulated the G cells: electrical vagal stimulation and pylorus ligation (fasted rats) raised the gastrin concentration transiently in both serum and microdialysate. Food intake induced a 2- to 3-fold increase in serum gastrin, while gastrin in antral microdialysate increased 10- to 15-fold. In unilaterally vagotomized rats (fasted, 3 days post-op.), food evoked a prompt peak gastrin release followed by a gradual decline on the intact side. On the vagotomized side of the antrum, the peak response seemed to be reduced while the microdialysate gastrin concentration remained elevated. Thus, unilateral vagotomy surprisingly raised the integrated gastrin response to food on the denervated side compared to the intact side, indicating that vagotomy suppresses an inhibitory as well as a stimulating effect on the G cells. While local infusion of atropine was without effect, infusion of the neuronal blocker tetrodotoxin (TTX) (which had no effect on basal gastrin) virtually abolished the food-evoked gastrin response and lowered the high microdialysate gastrin concentration in omeprazole-treated rats by 65%. We conclude that activated gastrin release, unlike basal gastrin release, is highly dependent on a neural input: 1) Vagal excitation has a transient stimulating effect on the G cells. The transient nature of the response suggests that the vagus has not only a prompt stimulatory but also a slow inhibitory effect on gastrin release. 2) Although vagal denervation did not affect the gastrin response to anacidity, the TTX experiments revealed that both food-evoked and anacidity-evoked gastrin release depends on neural input.
Antiulcerogenic activity of a crude hydroalcoholic extract and coumarin isolated from Mikania laevigata Schultz Bip
2005, Phytomedicine
The leaves of Mikania (Asteraceae) species are used in folk medicine as antispasmodic, antiulcerogenic and antirheumatic agents. Phytochemical screening of the crude hydroalcoholic 70% extract (CHE) of Mikania laevigata Shultz Bip. revealed coumarins, terpenes and organic acids. Antiulcerogenic activity of CHE was evaluated, employing different experimental models in rats, to discern the pharmacological mechanism of action. Both the antisecretory and the cytoprotection hypothesis were evaluated. The crude hydroalcoholic extract (1000 mg/kg body wt., vo) decreased the ulcerative lesion index produced by indomethacin, ethanol, stress and reserpine in rats by 85%, 93%, 82% and 50%, respectively. In the pyloric ligation model, a decrease of hydrogenionic concentration (53%) was observed, suggesting that the pharmacological mechanism has a relationship to antisecretory activity. The antisecretory mechanisms of CHE and the coumarin isolated from M. laevigata were confirmed by acid hypersecretion induced by histamine, pentagastrin and bethanechol. Duodenal administration of CHE (1000 mg/kg body wt.) and coumarin (100 mg/kg body wt.) inhibited only the gastric acid secretion produced by bethanecol. These results suggest that both CHE and coumarin may influence the secretion control mediated by the parasympathetic system.
Neurogenic stimulation of gastric acid secretion by the Na<sup>+</sup>,K<sup>+</sup>-ATPase inhibitor ouabain in mouse isolated stomach
1996, General Pharmacology
- 1.
  1. We have previously found the stimulatory effect of ouabain on gastric acid secretion. In the present study, we further studied the ouabain-induced acid secretion in mouse isolated stomach.
- 2.
  2. In the resting stomach preparation, ouabain produced a transient increase in basal acid secretion, which was followed by a fall to the level lower than the initial basal level.
- 3.
  3. The ouabain-induced acid secretion was abolished by tetrodotoxin or atropine, and was partially inhibited by hexamethonium or famotidine. High K⁺ solution potentiated the ouabain stimulation.
- 4.
  4. Endogenous ouabain has been recently identified in plasma of humans, but the physiological roles of this compound have not yet been defined. The present study in mouse isolated stomach showed that ouabain induced a transient increase in gastric acid secretion through the release of endogenous acetyl-choline, and subsequently inhibited acid secretion. It therefore seems likely that endogenous ouabain modifies gastric acid secretion in physiological and pathological conditions.
Stimulatory effect of muscimol on gastric acid secretion stimulated by secretagogues in vagotomized rats under anesthesia
1995, European Journal of Pharmacology
The effect of intravenous administration of muscimol, a GABA_A receptor agonist, on gastric acid secretion from perfused stomach was studied in vagotomized rats anesthetized with urethane. Muscimol did not stimulate acid secretion by itself. In contrast, muscimol dose dependently potentiated acid secretion induced by pentagastrin, bethanechol and direct vagal stimulation, but not histamine. Muscimol-potentiated acid secretion induced by pentagastrin and bethanechol was not influenced by pretreatment with atropine or cimetidine, respectively. Muscimol-potentiated acid secretion evoked by direct vagal stimulation was prevented by pretreatment with proglumide, a gastrin receptor antagonist. Muscimol-potentiated acid secretion evoked by bethanechol was dose dependently prevented by bicuculline methiodide, suggesting an involvement of peripheral GABA_A receptors. These results suggest that muscimol stimulates acid secretion under certain conditions, and that two mechanisms are involved in this effect. The effects of muscimol on acid secretion may be mediated by increasing the release of histamine by pentagastrin, bethanechol and direct vagal stimulation. In addition, muscimol would also be effective if muscarinic agents were already occupying muscarinic acetylcholine receptors on parietal cells.
Comparison of Effects of Famotidine on Vagally and Field-Electrically Stimulated Acid Secretion in the Isolated Mouse Whole Stomach
1995, The Japanese Journal of Pharmacology
Effects of famotidine on neuronally evoked acid secretion were investigated by means of vagal (at the lower esophagus level) and field-electrical stimulation (around the stomach) in the isolated mouse whole stomach preparation. Each of the electrical stimulations caused a frequency-dependent (1 to 20 Hz) increase in acid output, and the secretory response was abolished by tetrodotoxin or atropine. In the case of field stimulation, the acid secretion was not completely inhibited by hexamethonium. When 10 Hz frequency was applied with either vagal or field-electrical stimulation, the acid secretion was only partly inhibited by famotidine at doses of up to 30 μM. In contrast, the acid response to 2 Hz stimulation was almost completely inhibited by 1 μM famotidine. In the presence of neostigmine (30 nM), the 2 Hz vagally stimulated acid secretion became partly resistant to the effect of famotidine (10 μM). These results suggest that both vagally and field-electrically stimulated acid secretions have essentially the same characteristics and that the secretory mechanism through histamine release is exclusively dominant with weak stimulation, while the cholinergic mechanism on parietal cells is sufficient for reaching the maximal secretory response with strong stimulation.

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^∗: Present address: Baker Medical Research Institute, Commercial Road, Prahran, 3181 Victoria, Australia.

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The interaction of choline esters, vagal stimulation and H2-receptor blockade on acid secretion in vitro

Abstract

Life Sci.

Gastroenterology

Am. J. Med.

Production of acid secretion in the mouse isolated stomach by electrical field stimulation

Br. J. Pharmacol.

Analysis of anomalous pKB values for metiamide and atropine in the isolated stomach of the mouse

Br. J. Pharmacol.

Estimation of pKB values for histamine H2-receptor antagonists using an in vitro acid secretion assay

Br. J. Pharmacol.

Some quantitative uses of drug antagonists

Br. J. Pharmacol.

Characterisation of acid secretory responses of the rat isolated gastric mucosa to electric field stimulation

Br. J. Pharmacol.

The effect of metiamide on acid secretion stimulated by gastrin, acetylcholine and dibutyryl cyclic adenosine 3′,5′-mono-phosphate in the isolated whole stomach of the rat

Br. J. Pharmacol.

Selectivity of bethanechol on muscarinic receptors

J. Pharm. Pharmacol.

The interaction of choline esters, vagal stimulation and H₂-receptor blockade on acid secretion in vitro

Analysis of anomalous pK_B values for metiamide and atropine in the isolated stomach of the mouse

Estimation of pK_B values for histamine H₂-receptor antagonists using an in vitro acid secretion assay