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PubMed1988

Antihistaminic and antimuscarinic effects of amitriptyline on guinea pig ileal electrolyte transport and muscle contractility in vitro.

Amitriptyline, a tricyclic antidepressant, was tested for antimuscarinic and antihistamine effects against bethanechol and histamine-stimulated contractility and secretion in the guinea pig ileum in vitro. Comparisons were made with muscarinic-receptor antagonists, as well as with H1 and H2 histamine-receptor antagonists. Amitriptyline (0.01-5.0 microM) produced a parallel rightward shift in the concentration-response curves to histamine in muscle (Ki 0.4 nM) and mucosa (Ki 450 nM). The H1-receptor antagonists pyrilamine and diphenhydramine were less potent against histamine in the muscle and more potent against histamine in the mucosa than was amitriptyline. The H2-receptor antagonist cimetidine was ineffective in the muscle and mucosa. Amitriptyline (0.1-2 microM) also produced a parallel rightward shift in the concentration-response curve to bethanechol in muscle (Ki 133 nM) and mucosa (Ki 143 nM). Against bethanechol, in both tissues, atropine and 4-diphenylacetoxy-N-methyl piperidine methiodide were more potent competitive antagonists than was amitriptyline. Pirenzepine produced a competitive blockade of bethanechol in the muscle and a noncompetitive blockade in the mucosa. The data indicate that amitriptyline exerts more potent antihistaminic effects on guinea pig ileal muscle than the mucosa but that the tricyclic drug is equipotent as an antimuscarinic in both tissues.

Amitriptyline↗
PubMed1984

Adrenergic influence on gastric mucosal blood flow in gastric fistula dogs.

The aim of this study was to examine the influence of alpha-, beta- and dopaminergic receptors on gastric mucosal blood flow during "high", "normal", and "low" vagal conditions obtained by stimulation with bethanechol and pentagastrin and by parietal cell vagotomy respectively. During pentagastrin and bethanechol stimulation, a linear relationship between gastric acid secretion and mucosal blood flow was observed. During pentagastrin stimulation, dopamine (40 micrograms/kg/min) did not change the blood flow values while a decrease in acid secretion was found. During bethanechol stimulation dopamine (10 micrograms/kg/min) induced an increase in mucosal blood flow and a similar increase in acid secretion. If the dopamine infusion was preceded by alpha-receptor blockade, a pronounced increase in mucosal blood flow was observed without a similar increase in acid secretion. beta-adrenergic stimulation (isoprenaline) reduced the pentagastrin and bethanechol stimulated gastric acid secretion without a similar decrease in mucosal blood flow. beta-blockade (propranolol) increased the pentagastrin stimulated gastric acid secretion in parietal cell vagotomized dogs. This increase in acid output was preceded by an initial increase in mucosal blood flow and in the last two periods a decrease in blood flow. alpha-Blockade (phentolamine) reduced the pentagastrin stimulated gastric acid secretion and gastric mucosal blood flow but the ratio between blood flow and acid secretion was increased, indicating a relatively increasing effect on mucosal blood flow. One may conclude that blood flow and acid secretion are not unconditionally linked and that at least two different mechanisms are involved in blood flow changes in the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Effects of glucose deprivation on the contractile response of the rabbit bladder to repetitive stimulation.

The urinary bladder requires an adequate energy supply to maintain contractile function. The primary metabolic fuel is glucose. Through glycolysis and oxidative phosphorylation, high energy phosphates are generated, which in turn supply the metabolic energy for the contractile activities of the urinary bladder. The aim of this study was to determine the effects of glucose deprivation and recovery from glucose deprivation on the phasic and tonic components of the contractile responses of rabbit bladder strips to field stimulation, bethanechol, and KCl. The results can be summarized as follow: In response to glucose deprivation, (1) the tonic responses to field stimulation, bethanechol, and KCl all decreased at a significantly greater rate than the phasic responses; (2) the phasic and tonic responses to field stimulation were both reduced to less than 10% of control within 70 minutes of initiating glucose deprivation; (3) the tonic responses to bethanechol and KCI were reduced to approximately 10% of control within 180 minutes whereas the phasic responses remained stable at 40 and 30%, respectively; and (4) glucose replacement stimulated a rapid and nearly complete recovery of the phasic and tonic components of the responses to field stimulation, bethanechol, and KCI. These results indicate that the tonic responses to all forms of stimulation are more sensitive to glucose deprivation than the phasic responses.

Animals↗
PubMed1983

Biphasic action of intravenous ethanol on dog exocrine pancreatic secretion.

The effect of a 20-min intravenous infusion of 1 g/kg of ethanol on a 15% (w/w) solution in isotonic saline on pancreatic secretion was determined in six conscious Beagle dogs provided with Thomas cannulae. Ethanol was given on a background of a prolonged infusion of 0.5 CU/kg/hr of secretin alone or secretin plus either different doses of cerulein (12.5-200 ng/kg/hr), 3 micrograms/kg/hr of pentagastrin, or 200 micrograms/kg/hr bethanechol. Intravenous ethanol had a biphasic action on pancreatic secretion: inhibition during the first 40 min followed by stimulation. When compared to control experiments with intravenous infusion of saline, the inhibition was statistically significant only for volume and bicarbonate output against a background of pentagastrin and for protein output against a background of bethanechol. We propose that alcohol inhibits acetylcholine-mediated protein secretion. The delayed stimulatory effect of ethanol was statistically significant for both ecobolic (protein output) and hydralatic (water and bicarbonate) secretion during infusion of secretin plus 12.5-25 ng/kg/hr cerulein, but not with doses of 50 ng/kg/hr. Although the plateau of secretion before alcohol was roughly similar in the experiments using cerulein and bethanechol, ethanol inhibited protein output and had no effect on bicarbonate output during stimulation with bethanechol. Therefore, the effects of alcohol on pancreatic secretion are influenced by both the type of stimulation and its intensity (dosage).

Animals↗
PubMed1981

Apneustic respiration normalized by an atypical cholinergic drug action in cats.

Cats were anesthetized with a mixture of pentobarbital and barbital given intraperitoneally and vagotomized. All animals were pretreated with atropine i.v. which blocked conventional muscarinic receptors and at the same time revealed atropine-insensitive sites whose stimulation by the cholinergic drug, bethanechol, was earlier found to produce respiratory analepsis. Respiration was recorded by pneumotachograph and intrapleural cannula. Apneustic breathing was produced by placing electrolytic lesions in the pneumotaxic area or by injecting a local anesthetic agent into the cerebrospinal fluid. Experiments were performed under isocapnic conditions. Bethanechol, administered intracerebro-ventricularly, restored regular breathing and increased the tidal volume in a dose-related manner within minutes of its injection. In cats with lesions, the expiratory pause generally decreased first and was followed by shortening of the inspiratory plateau. In cats made apneustic by intracerebro-ventricular injection of procaine, bethanechol acted competitively to normalize the distorted waveshape. The central excitant drug pentylenetetrazol was given intravenously for comparison with bethanechol. Apneustic breathing was partially corrected by pentylenetetrazol through a facilitatory influence on the brain stem interpreted to be independent of its convulsant action. These experiments demonstrate correction of pathological breathing by two chemically unrelated agents which share the ability to increase central excitatory state.

Animals↗
PubMed1983

Comparative pharmacological response of an in vitro whole bladder preparation (rabbit) with response of isolated smooth muscle strips.

Although much of our knowledge of the pharmacological response of the urinary bladder comes from in vitro muscle strip studies, it is not clear if these studies can be directly correlated with bladder function. We have compared the pharmacological response of an in vitro whole bladder model with the response of the standard muscle strip technique. The whole bladder model has the advantage of being able to measure both the isometric contractile response to drugs as well as a functional response in which the bladder can empty in the presence of a constant resistance. The results of these studies may be summarized as follows: 1) bethanechol was equipotent in contracting the muscle strips and in the closed whole bladder model; 2) at low and intermediate bladder volumes, the bladder fully emptied at concentrations of bethanechol significantly below the concentration required for maximal contraction; 3) isoproterenol, a potent beta-adrenergic agonist, stimulated a strong relaxation in muscle strips, whereas the whole bladder responded very poorly to isoproterenol; 4) in muscle strips isoproterenol strongly antagonized bethanechol contraction, whereas, in the whole bladder system, isoproterenol did not significantly antagonize bethanechol contraction; 5) methoxamine and adenosine triphosphate produced a moderate, equipotent contraction in both models.

Adenosine Triphosphate↗
PubMed1982

Metabolic and contractile effects of anoxia on the rabbit urinary bladder.

The in vitro metabolic and contractile effects of anoxia and glucose deprivation on the rabbit urinary bladder were studied. The exposure of isolated strips of rabbit urinary bladder to a glucose deficient medium equilibrated with nitrogen rather than with oxygen resulted in 1) a rapid decrease in baseline tension, 2) a progressive decrease in the intracellular concentration of adenosine 5'-triphosphate (ATP) and progressive increases in the concentrations of adenosine 5'-monophosphate and adenosine 5'-diphosphate, 3) a rapid decrease in the ability of bethanechol to stimulate contractility, and 4) the inability of bethanechol to maintain a sustained increase in contractile force. Recovery from a 60-minute exposure of bladder strips to anoxia was characterized by a rapid recovery of the ability of the bladder to respond to bethanechol (50 per cent recovery occurring within 15 minutes) and a slightly slower recovery of the intracellular ATP level. Both the contractile response to bethanechol and the intracellular concentration of ATP returned to control levels within 60 minutes after the termination of anoxia.

Adenosine Diphosphate↗
PubMed1999

Effects of ethanol and its metabolite acetaldehyde on responses of the rat bladder.

OBJECTIVE: To investigate the pharmacological effects of ethanol and its metabolite acetaldehyde on isolated rat bladder muscle, and thus assess the potential influence of ethanol ingestion on the risk of urinary retention in patients with benign prostatic hyperplasia. MATERIALS AND METHODS: Isometric tension changes of isolated rat bladder muscle strips were recorded in an organ bath using a pressure transducer. The acute or prolonged effects of ethanol (1-4%) or acetaldehyde (0.01, 0.1 or 1 mmol/L) were assessed on resting tension, electrical field stimulation (EFS), and bethanechol- (0.5 mmol/L), ATP- (2 mmol/L) or KCl- (127 mmol/L) induced contraction. To determine the mechanism of acetaldehyde-induced stimulation, an antihistamine, diphenhydramine was used after bethanechol stimulation. RESULTS: At the concentrations used, ethanol and acetaldehyde did not change the pH of the bathing medium. The resting tension of the muscle was not changed by ethanol, and acetaldehyde caused only a small increase in baseline tone at 1 mmol/L. Incubation with ethanol or acetaldehyde significantly suppressed contractility induced by EFS, bethanechol, ATP or KCl at each concentration (P<0.05). Contractions induced by all drugs were not changed significantly by the acute application of ethanol and the acute application of acetaldehyde did not affect contractions induced by ATP or KCl. However, EFS- or bethanechol-induced contractions were significantly enhanced (P<0. 05). The acetaldehyde-induced effects were completely blocked by the H1 antagonist, diphenhydramine (10 micromol/L). CONCLUSIONS: Ethanol did not affect resting tension but acetaldehyde and ethanol suppressed bladder muscle contractions. However, direct acetaldehyde-stimulation may release histamine and enhance contractility. This suggests that chronic alcoholism rather than acute intoxication is more likely to provoke urinary retention.

Acetaldehyde↗
PubMed1997

Lack of anticholinergic activity by baicalin in the isolated trachea of guinea pig.

The anticholinergic effect of baicalin on the trachea from asthmatic guinea pig had been described elsewhere. Using 1 x 10(-5) M bethanechol to induce contraction in the isolated trachea from non-asthmatic guinea pig, baicalin below 1 x 10(-4) M was unable to attenuate the bethanechol-induced tracheal contraction; however, 1 x 10(-4) M baicalin was demonstrated to increase the tracheal contraction in the presence of bethanechol. Baicalin (1 x 10(-4) M) was also able to induce tracheal contraction in the absence of bethanechol, and this baicalin-induced tracheal contraction was shown to be atropine-sensitive. These data suggested that the baicalin effect on the isolated trachea from non-asthmatic guinea pig was not anticholinergic in nature.

Animals↗
PubMed2002

Insulin inhibits secretin-induced pancreatic bicarbonate output via cholinergic mechanisms.

INTRODUCTION: Exogenous insulin inhibits secretin-stimulated pancreatic bicarbonate output via a dose-dependent mechanism; this effect is prevented by pancreatic denervation. AIMS: To investigate possible cholinergic mediation, we examined the effect of bethanechol on secretin-stimulated pancreatic secretion during euglycemic, hyperinsulinemic clamp. METHODOLOGY: In four dogs with chronic pancreatic fistulas, euglycemic, hyperinsulinemic clamp (1.25 mU/kg/min) was begun after a 30-minute basal period; computer-assisted glucose administration maintained euglycemia. Control studies were performed with volume-matched and rate-matched vehicle infusion. After 1 hour, secretin infusion was begun at a dosage of 16 ng/kg/h; the dose was doubled every 30 minutes. The studies were then repeated during background bethanechol infusion (90 microg/kg/h) begun 30 minutes after clamp initiation. Pancreatic juice was analyzed for bicarbonate and protein; serum samples were analyzed for glucose and insulin. RESULTS: Exocrine outputs and serum glucose and insulin levels did not differ in the basal period. Insulin levels were significantly elevated during the euglycemic, hyperinsulinemic clamp (62 microU/mL versus 12 microU/mL; p < 0.01); glucose levels did not differ. As before, secretin-induced bicarbonate output was inhibited by euglycemic, hyperinsulinemic clamp. The inhibitory effect of insulin was reversed by bethanechol. Despite the euglycemic, hyperinsulinemic clamp, secretin-induced bicarbonate output was potentiated by bethanechol at higher secretin doses (p < 0.05). CONCLUSION: These data confirm that cholinergic mechanisms mediate insulin's inhibition of secretin-induced pancreatic bicarbonate output.

Animals↗
PubMed1978

Inhibition by metiamide of secretagogue-induced gastric acid secretion in the conscious Heidenhain pouch rat.

1. The inhibition by metiamide of gastric of gastric acid secretion in response to histamine, pentagastrin and bethanechol has been investigated in the conscious Heidenhain pouch rat. 2. Histamine alone stimulated only a low rate of acid secretion. This response was markedly potentiated in the presence of mepyramine. 3. Metiamide at a dose of 0.15 mumole . kg-1 . min-1 I.V. significantly inhibited the acid secretory responses to histamine (in the presence of mepyramine) and pentagastrin. In each case the inhibition of acid output was the result of a significant decrease in both secretory volume and acid concentration. 4. Metiamide at a dose of 0.15 mumole . kg-1 . min-1 I.V. did not inhibit bethanechol-stimulated acid secretion. Increasing the dose of metiamide to 1.0 mumole . kg 1 . min-1 I.V. did produce a significant inhibition. In contrast with histamine and pentagastrin, metiamide inhibited bethanechol-stimulated secretion only by reducing acid concentration; there was no significant decrease in the gastric secretory volume. 5. It is concluded that these results are consistent with the view that histamine and pentagastrin share a common pathway in stimulating gastric acid secretion in the rat. The role of histamine in the control of bethanechol-stimulated acid secretion remains unclear.

Animals↗
PubMed2006

Muscarinic regulation of ether-a-go-go-related gene K+ currents in interstitial cells of Cajal.

The interstitial cells of Cajal (ICC) of the myenteric plexus generate a set of currents that evoke a pacemaker potential that sets the initial conditions for the contraction frequency and duration of the electrically coupled intestinal musculature. The synapse-like contacts between ICC and myenteric motor nerves highlight the potential role of the enteric nervous system in regulating the pacemaking currents in ICC. The objective of the present study was to investigate muscarinic regulation of the ether-a-go-go-related gene (ERG) K(+) current. Immunoreactivity of the M(3) receptor (M(3)R) but not the M(2) receptor was detected on murine jejunal ICC-Auerbach's plexus (ICC-AP). The muscarinic agonist bethanechol reduced hyperpolarization-evoked peak ERG currents at -100 mV by 23 +/- 1% and increased both fast and slow time constants of deactivation, resulting in increased steady-state currents between -55 and -35 mV. Bethanechol also increased depolarization-evoked steady-state currents by 59 +/- 10% at -40 mV, whereas currents were decreased at potentials positive to 0 mV. The half-maximal voltage of activation was shifted 11.9 mV leftward. Interestingly, the time constant of activation increased only at -40 mV. Atropine prevented and 2 muM E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl-4-(methylsulfonylaminobenzoyl)piperidine] inhibited bethanechol-affected currents. The effect of bethanechol was mimicked by protein kinase C (PKC) activation and diminished by PKC inhibition. Our results indicate that the ERG K(+) channel in ICC is affected by stimulation of muscarinic receptors, probably the M(3)R, via a PKC-dependent mechanism. Modulation of the ERG K(+) current in ICC-AP will affect the kinetics of pacemaking in the intestinal musculature.

Animals↗
PubMed1999

Cholinergic effects on human gastric motility.

BACKGROUND: Cholinergic regulation of chronotropic (frequency) and inotropic (force) aspects of antral contractility and how these impact on gastric emptying are not well delineated. AIMS: To determine the effects of cholinergic stimulation and inhibition on myoelectric, contractile, and emptying parameters of gastric motility. METHODS: Ten normal subjects underwent three studies each, using simultaneous electrogastrography (EGG), antroduodenal manometry, and gastric emptying with dynamic antral scintigraphy (DAS). After 30 minutes of baseline fasting manometry and EGG, subjects received saline intravenously, atropine (0.6 mg then 0.25 mg/hour intravenously), or bethanechol (5 mg subcutaneously). This was followed by another 30 minutes' recording and by three hours of postprandial recording after ingestion of a technetium-99m labelled solid meal. RESULTS: During fasting, atropine decreased, whereas bethanechol increased, the antral manometric motility index and EGG power. Postprandially, atropine decreased the amplitude of antral contractions by DAS, decreased the postprandial antral manometric motility index, and slowed gastric emptying. Atropine caused a slight increase in postprandial frequency of antral contractions by DAS and gastric myoelectrical activity by EGG. Bethanechol slightly increased the amplitude, but slightly decreased the frequency of antral contractions by DAS and decreased the frequency of gastric myoelectrical activity by EGG, with no significant increase in the motility index or gastric emptying. CONCLUSIONS: Cholinergic antagonism with atropine reduces antral contractility and slows gastric emptying. Cholinergic stimulation with bethanechol increases antral contractility, but decreases the frequency of antral contractions, without altering the antral motility index or gastric emptying.

Adult↗
PubMed1981

Calcium fluxes in isolated pancreatic acini: effects of secretagogues.

45Ca2+ exchange and total calcium content were measured in isolated mouse pancreatic acini. 45Ca2+ uptake could be described as the sum of a constant and a single exponential kinetic component; about 60% of total acinar calcium was exchangeable. Stimulation by bethanechol increased 45Ca2+ uptake, but the time course of uptake could be fit only by the addition of a more rapid kinetic component without any change in the total exchangeable Ca2+. 45Ca2+ washout after 1-h loading could be fit as the sum of two exponential components. Stimulation increased the rate of 45Ca2+ washout with the appearance of a third and more rapid kinetic component. There was not, however, a good correspondence between the exponential constants measured in uptake and washout protocols in unstimulated acini. Exponential constants were also affected by the concentration of calcium in the medium, further indicating the presence of nonlinearities in 45Ca2+ exchange. The dose-response relationships were similar for bethanechol stimulation of 45Ca2+ uptake and amylase release, whereas stimulation of 45Ca2+ washout reached a maximum at a higher concentration of bethanechol. Both 45Ca2+ uptake and analytical measurement of total Ca2+ showed a rapid drop in acinar Ca2+ content followed by a gradual reuptake on stimulation by bethanechol. It is concluded that the initial primary effect of secretagogues is to increase Ca2+ efflux, which is interpreted to be the result of release of sequestered calcium into the cytosol.

Amylases↗
PubMed2001

Cholinergic stimulation enhances colonic motor activity, transit, and sensation in humans.

The cholinesterase inhibitor neostigmine indirectly stimulates muscarinic M(1)/M(2)/M(3) receptors, thereby reducing colonic distension in acute colonic pseudo-obstruction. We investigated the dose-response profile for the colonic sensorimotor effects of neostigmine and bethanechol, a direct muscarinic M(2)/M(3) agonist in humans. A barostat-manometric assembly recorded phasic pressures, tone, and pressure-volume relationships (compliance) in the descending colon and rectum of 30 healthy subjects who received intravenous neostigmine (0.25, 0.75, or 1.5 mg; n = 15) or subcutaneous bethanechol (2.5, 5, or 10 mg; n = 15). Sensation to luminal distension was also assessed. Thereafter, the effects of neostigmine and bethanechol on colonic transit (geometric center) were compared with those of saline by scintigraphy in 21 subjects. Both drugs increased colonic phasic pressure activity, reduced rectal compliance, and enhanced urgency during rectal distension. Neostigmine also reduced colonic and rectal balloon volumes, reflecting increased tone by an average of 12% and 25% for the highest dose, respectively. Only neostigmine reduced colonic compliance, accelerated colonic transit [mean geometric center at 90 min 2.5 vs. 1.0 (placebo)], and increased pain perception during colonic distension. We conclude that neostigmine has more prominent colonic motor and sensory effects than bethanechol. Moreover, neostigmine induces coordinated colonic propulsion, perhaps by stimulating muscarinic M(1) receptors in the myenteric plexus.

Adult↗
PubMed1975

Ca++ and pancreatic amylase release.

The effects of Ca'++ on release of amylase by mouse pancreas in vitri was studied. The cholinergic agonist bethanechol was depressed about 50% in O Ca'++ medium. When pancreatic fragments were superfused with O Ca'++ medium, bethanechol still produced a normal stimulation of amylase release after half of the total tissue Ca'++ was washed out. This Ca'++ loss included both extracellular and some intracellularCa'++. Uptake and equilibration of '45Ca'++ into pancreatic fragments was multiphasic, with total equilibration with stable Ca'++ still not reached after 3 h. Addition of bethanechol had no effect on the rate of '45Ca uptake and equilibration. '45Ca'++ efflux was not influenced by superfision in O Ca'++ medium, while thestimulation of '45Ca'++ efflux by bethanechol was enhanced. It is concluded that extracellular Ca'++ and/or Ca'++ influx is not of major importance in triggering pancreatic enzyme release, but that extracellular Ca'++ may regulate the release process thus accounting for the parallel changes in unstimulated and stimulated amylase release.

Amylases↗
PubMed1996

Effect of thapsigargin on the contractile response of the normal and obstructed rabbit urinary bladder.

Excitation-contraction coupling is achieved by translocation of calcium from the extracellular space as well as by the release of calcium from intracellular stores. Thapsigargin has been shown to selectively block the sarcoplasmic Ca-ATPase, thereby preventing the reuptake of calcium into intracellular stores and the participation of these calcium storage sites in the contractile response to stimulation. The current study determined the effect of thapsigargin on the contractile response to field stimulation, bethanechol, and KCl in control rabbit bladders and bladders obtained from rabbits subjected to partial outlet obstruction. Partial bladder outlet obstruction resulted in a marked increase in bladder mass and in significant decreases in the contractile response to field stimulation, bethanechol, and KCl. Thapsigargin (5-40 microM) had no effect on the contractile responses of bladder strips isolated from control rabbits to field stimulation, bethanechol, or KCl. However, bladder strips isolated from obstructed rabbits showed a significant concentration-dependent decrease in the contractile response to field stimulation in the presence of thapsigargin. Thapsigargin had no effect on the contractile responses of bladder strips isolated from obstructed rabbits to either bethanechol or KCl. In general, the data described in this study support our current hypothesis: as smooth muscle cells enlarge (hypertrophy) and the cell volume increases, there is an increased dependence on the release of intracellular calcium from the sarcoplasmic reticulum to mediate the contractile response to field stimulation.

Animals↗
PubMed1991

Differences in the antisecretory actions of the proton pump inhibitor AG-1749 (lansoprazole) and the histamine H2-receptor antagonist famotidine in rats and dogs.

Antisecretory effects of a substituted benzimidazole, (+/-)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were compared with those of a histamine H2-receptor antagonist, famotidine. AG-1749 inhibited acid formation regardless of the stimulant in isolated canine parietal cells, while famotidine inhibited the histamine-stimulated acid formation selectively. In pylorus-ligated rats, AG-1749 suppressed basal acid secretion, histamine-, bethanechol-, pentagastrin-, 2-deoxy-D-glucose- and stress (restraint and water-immersion)-induced acid secretion; ID50 values were 1.0-6.0 mg/kg. On the other hand, famotidine only partially inhibited the acid secretion induced by 2-deoxy-D-glucose or stress, although it suppressed the acid secretion stimulated by other secretagogues several times more potently than AG-1749. The antisecretory effect of AG-1749 lasted longer than that of famotidine, especially in the case of bethanechol-stimulated acid secretion. In Heidenhain pouch dogs, both AG-1749 and famotidine potently inhibited histamine-, bethanechol-, pentagastrin- and peptone meal-stimulated acid secretion, but the inhibitory effect of famotidine was short-lived in the case of bethanechol- and pentagastrin-stimulated acid secretion. These results suggest that AG-1749 persistently inhibits acid secretion induced by both peripheral and central stimuli and suggest that the antisecretory effect of famotidine depends on the nature of the stimuli.

2-Pyridinylmethylsulfinylbenzimidazoles↗