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At least 19 recordsLinked to original sources
PubMed1989

Effect of cimetropium bromide and other antispasmodic compounds on in vitro guinea-pig gallbladder.

The effect of cimetropium bromide, a new antimuscarinic compound, on bethanechol- and electrically-induced contractions was studied on isolated guinea-pig gallbladder. Atropine and two other widely employed antispasmodics (i.e., rociverine and octylonium bromide) were employed as reference compounds. Cimetropium and atropine proved to be competitive antimuscarinics, their pA2 being 7.77 +/- 0.14 and 8.31 +/- 0.14, respectively. On the contrary, rociverine displayed a dual effect being a competitive antagonist at low (up to 10(-5) mol/l) and a mixed one at high (greater than 10(-5) mol/l) concentrations. When tested against bethanechol- and electrically-induced contractions, all the compounds, with the exception of octylonium bromide, showed a concentration-dependent relaxant effect. In both experimental conditions, the potency of cimetropium was of the same order of magnitude as that of atropine and 150-200 times higher than that of rociverine. These data, together with the reported activity on human gallbladder in vivo and the well known involvement of cholinergic system in the control of gallbladder motility, could represent the rationale for the clinical use of cimetropium in the treatment of biliary colics as well as spasms of biliary tree.

Animals↗
PubMed1989

Inhibitory effects of DF 594, a new antispasmodic agent, on intestinal motility in the dog.

DF 594, 11-(N-methylnipecotyl)-6,11-dihydro-5H-pyrido[2,3-b]-1,5-benzod iazepin-5-one hydrochloride, is a new antimuscarinic compound endowed with high affinity for intestinal muscarinic receptors and showing potent inhibitory effects on intestinal motility. This study investigated the intestinal motor effects of DF 594 in fasting, conscious dogs, chronically fitted with electrodes and strain gauges along the small bowel. In a first series of experiments, we assessed the antispasmodic activity of the compound by comparing the ability of intravenous DF 594 or atropine to antagonize the stimulatory effect of bethanechol (100 micrograms/kg s.c.). ED50 values for inhibition of bethanechol-stimulated contractions were 13.9 (8.8-21.8) and 4.0 (1.8-8.7) micrograms/kg for DF 594 and atropine, respectively. In a second series of experiments, we evaluated the effects of intravenous DF 594 and atropine on the migrating motor complex (MMC), monitoring heart rate as well. Similarly to atropine (30-100 micrograms/kg), DF 594 (100-300 micrograms/kg) blocked the further migration of an ongoing MMC and significantly delayed the onset of the following MMC. Unlike atropine, DF 594 had only a minor effect on heart rate at the highest dose tested (300 micrograms/kg). These data indicate that DF 594 is an effective antispasmodic agent at doses lower than those required to interfere with the MMC and is also less likely than atropine to induce cardiac side effects.

Animals↗
PubMed1986

The effect of the new H2-receptor antagonist mifentidine on gastric secretion, gastric emptying and experimental gastric and duodenal ulcers in the rat: comparison with cimetidine and ranitidine.

The new H2-receptor antagonist mifentidine (DA 4577) was tested for its antisecretory and gastric motor effects in comparison with cimetidine and ranitidine. The Shay rat preparation (5 h) was used for studying gastric secretion; the gastric emptying of a liquid meal was chosen for studying gastric motility. All the three compounds inhibited acid secretion in a dose-dependent fashion. Calculated ED50s were 2.3, 12.2 and 92.8 mg X kg-1 for mifentidine, ranitidine and cimetidine, respectively. Therefore, in this animal model, mifentidine was about 40 times more potent than cimetidine and 5 times more potent than ranitidine. As far as gastric emptying is concerned, the effect of equiactive antisecretory doses (i.e. the respective ED50s calculated from the previously established dose-response curves) of all the three antagonists was completely different. Cimetidine delayed emptying rate, whereas ranitidine accelerated it and mifentidine was completely ineffective. However, at higher doses, also this compound affected emptying rate by reducing it dose-dependently. Gastric and duodenal ulcers were induced in the rat by dimaprit (100 mg X kg-1 intravenously) and cysteamine (250 mg X kg-1 subcutaneously), respectively. As far as gastric ulcer is concerned, the ED50s (the effective dose which protected 50% of the animals from lesions) were 0.23, 4.40 and 9.70 mg X kg-1 for mifentidine, ranitidine and cimetidine, respectively. As regards duodenal ulcer, the ED50 was 4.48 for mifentidine and 150.00 mg X kg-1 for ranitidine. In this animal model, the efficacy of cimetidine was very low. Therefore an ED50 could not be determined. In conclusion, results of the present investigation demonstrated that mifentidine is a potent antisecretory compound and an effective anti-ulcer agent in the rat.

Animals↗
PubMed1979

Potentiation and inhibition of ganglionic transmission by ruthenium red.

The effect of ruthenium red, 2.5 to 5 muM, on ganglionic transmission in rat superior cervical ganglia and frog abdominal ganglia were studied in vitro. In rat ganglia, ruthenium red caused a spontaneous firing of ganglia cells, and an increase in the amplitude and duration of the compound action potential following a single stimulus volley. However, transmission following a conditioning volley or a repetitive stimulus train to the preganglionic nerve was depressed up to 60 sec. The asynchronous firing caused by bethanechol was potentiated by ruthenium red. In the frog, ruthenium red caused repetitive firing of ganglion neurons following either orthodromic or antidromic stimulation. It is suggested that the potentiation of the single potential and the spontaneous firing are due to a ruthenium red-induced increase in intracellular calcium concentration. The depression of transmission may be due to a temporary depletion of readily releasable acetylcholine. It is also suggested that ruthenium red has an effect on the postsynaptic membrane.

Action Potentials↗
PubMed1977

Effects of membrane stabilizers on pancreatic amylase release.

Compounds with membrane stabilizing activity were studied as to their ability to affect pancreatic amylase release and the steps in the stimulus-secretion coupling process. Chlorpromazine, propranolol, and thymol were all found to inhibit bethanechol-stimulated amylase release and at slightly higher concentrations to induce release regardless of the presence of the secretagogue. This biphasic effect was similar to that found previously for the local anesthetic tetracaine. Release by high concentrations of propranolol and tetracaine was accompained by ultrastructural evidence of cell damage. Membrane stabilizers at concentrations which inhibited amylase release were shown to block bethanechol-induced depolarization and stimulation of 45Ca++ efflux although the drugs alone partially depolarized pancreatic cells. Release of amylase induced by Ca++ introduced by the ionophore A23187 was also abolished. The findings indicate that membrane stabilizers independently inhibit the steps leading to a rise in intracellular Ca++ and the subsequent Ca++-activated amylase release.

Amylases↗
PubMed1986

Effect of omeprazole on gastric acid secretion by the rat isolated stomach.

The inhibitory effect of omeprazole has been investigated on the isolated gastric fundus from immature rats. Omeprazole (10(-7)-10(-5) M) inhibited basal acid secretion, conversely from H2-receptor antagonists, antimuscarinic compounds and calcium antagonists; the effect was mimicked only by KSCN (3 X 10(-4)-3 X 10(-2) M). Omeprazole (10(-6)-10(-5) M) caused an insurmountable antagonism of the hypersecretion induced by histamine and bethanechol, whereas it competitively antagonized the secretory response to isoprenaline and dibutyryl cAMP. Experiments carried out in low calcium media showed that calcium ions did not significantly affect the inhibitory potency of omeprazole when tested on basal acid secretion, whereas low calcium solutions enhanced the action of omeprazole against histamine-induced hypersecretion. The above data confirmed the potent antisecretory activity of omeprazole in different experimental conditions in which the common antisecretagogues are without effect and pointed out the novel site of action in the control of gastric acid secretion at intracellular level.

Animals↗
PubMed1990

Gastric acid inhibitory action of a GABA-related compound, 3-amino-3-phenylpropionic acid, in the rat.

The acid inhibitory properties of 3-amino-3-phenylpropionic acid, a structural GABA analogue, were studied in the perfused rat stomach preparation. 3-Amino-3-phenylpropionic acid, 10 and 30 mg/kg i.v., dose dependently suppressed the gastric acid secretion induced by baclofen (2 mg/kg s.c.). This secretagogue action had been shown to be unaffected by either GABAA or GABAB receptor antagonists. The i.v. administration of 3-amino-3-phenylpropionic acid (3 and 10 mg/kg) was also effective to abolish the acid stimulatory effects of muscimol (1 mg/kg i.v.) and 2-deoxy-D-glucose (200 mg/kg i.v.). 3-Amino-3-phenylpropionic acid, even at the high dose (30 mg/kg i.v.) had no influence on the acid output in response to histamine and bethanechol. Furthermore, 3-amino-3-phenylpropionic acid had no significant effect on the acid secretion induced by electrical vagal stimulation. These results indicate that the antisecretory effect of 3-amino-3-phenylpropionic acid is different from those of antimuscarinics, H2-receptor antagonists and vagal blockade. Together, the results suggest that 3-amino-3-phenylpropionic acid might act in the brain to inhibit central regulation mechanisms of gastric acid secretion, probably through GABA mechanisms.

Animals↗
PubMed1990

Hexocyclium derivatives with a high selectivity for smooth muscle muscarinic receptors.

1. The affinity of a number of derivatives of the muscarinic antagonist, hexocyclium, containing an amidine cationic head, for guinea-pig cardiac and ileal receptors was investigated. 2. All the compounds studied displayed a greater affinity for muscular than for cardiac muscarinic receptors. 3. The 5 fold ileal selectivity of hexocyclium was increased by a number of chemical substitutions. The largest discrimination between receptors (about 200 fold) was found for the formamidine derivative. 4. The selectivity displayed by the hexocyclium derivatives stemmed from a greater decrease in affinity towards cardiac as compared to ileal receptors.

Animals↗
PubMed1991

[Effects of NIK-228 on gastric acid secretion in rats using the congo red sprayed method].

We have reported the antiulcer activities of a new compound that we named NIK-228 (3-hydroxy-methyl-2-methylimidazo [2, 1-b] benzothiazole). In the present report, we studied the antisecretory effects of NIK-228 on basal and stimulated gastric acid secretion using the Congo red sprayed method. Male Wistar rats (200 to 250 g) were used after 24 hr of fasting (without water). NIK-228, atropine and cimetidine were administered orally or intravenously 1 hr before operation for Congo red spraying. NIK-228 (100 mg/kg, p.o.), atropine (5 mg/kg p.o.) and cimetidine (100 mg/kg, p.o.) all inhibited basal gastric acid secretion. Oral administration of NIK-228 and atropine inhibited gastrin, 2-deoxy-D-glucose (2-DG) and bethanechol-induced acid secretion, but didn't inhibit histamine-induced acid secretion. Cimetidine inhibited all of histamine, gastrin, 2-DG and bethanechol-induced acid secretion. In vagotomized rats, oral and intravenous administration of atropine both inhibited bethanechol-induced acid secretion, but NIK-228 was not inhibited. These results suggested that antisecretory effects of NIK-228 were caused by the central vagal systems.

Animals↗
PubMed1975

Acid-secretory effects of pentagastrin, histamine, urecholine, DBcAMP, and cBMP in isolated stomachs of fed and fasted rats.

Pentagastrin, histamine, urecholine, DBcAMP, and cGMP were all potent stimulants of acid secretion in the isolated stomach of the fed rat. With the exception of histamine and cGMP, all of these compounds were inactive when the stomach of the fasted rat was used. Pentagastrin was most effective when given on the serosal surface while histamine was equally potent whether it was added to the mucosal or serosal surface of the isolated stomach. The test would appear to be a relatively simply, but effective system for studying the basic mechanisms of action of several important secretagogues in the rat.

Animals↗
PubMed1992

Effect of pinacidil on spontaneous and evoked contractile activity.

Uninhibited bladder contractions have been associated with a variety of bladder dysfunctions including outlet obstruction, neurogenic bladder, incontinence, and other neurologic and nonneurogenic bladder disorders. One class of compounds that is gaining popularity and support for the treatment of hyperreflexia is potassium channel openers, such as pinacidil and cromakalim. In general, these agents act by hyperpolarizing the smooth muscle membrane, resulting in an increase in membrane stability which in turn would be expected to inhibit spontaneous and evoked contraction. It is the purpose of this study to compare the potency and selectivity of pinacidil at inhibiting both hyperreflexia in vivo, and several forms of in vitro contractile stimulation in the rabbit. The following is a summary of the results. (1) Pinacidil is an effective inhibitor of hyperreflexia in the in vivo rabbit model. (2) Pinacidil is a substantially more potent inhibitor of the amplitude of the hyperreflexia than the frequency. (3) Pinacidil was substantially more potent at inhibiting the contractile response to 2-Hz stimulation than to 32-Hz stimulation, but was equally effective at inhibiting field stimulation of the bladder base and body. (4) Pinacidil was significantly more potent at inhibiting the peak response to field stimulation than the rate of tension generation. (5) Pinacidil was equally potent and effective at inhibiting the phasic and tonic components of the response to field stimulation. (6) Pinacidil was a more potent inhibitor of methoxamine stimulation of the bladder base than bethanechol stimulation of the bladder body. (7) Pinacidil was a noncompetitive or mixed inhibitor of both methoxamine and bethanechol stimulation, whereas it was a competitive inhibitor of KCl stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Intracerebroventricular bethanechol for Alzheimer's disease. Variable dose-related responses.

Five male patients participated in a pilot open-label study of dose-related aspects of response to intracerebroventricular bethanechol in Alzheimer's disease. No patient had remission of symptoms, but three patients improved symptomatically and on tests of memory. Improvement was evident over a restricted range of doses for each subject, and symptoms were worse at doses below and above the optimal range. There was little overlap in the range of doses producing improvement among these three. Two patients had no consistent improvement in memory, and agitation, depression, paranoia, and seizures developed during treatment. Qualitative differences and variability in dosages producing responses complicate the identification of true drug response in the treatment of Alzheimer's disease.

Alzheimer Disease↗
PubMed1992

Cortical biopsy in Alzheimer's disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Intraventricular Bethanecol Study Group.

Neurochemical assessments were performed on biopsy samples taken from the right frontal lobe of patients diagnosed with Alzheimer's disease (AD), before the implantation of a ventricular catheter and pump assembly for the infusion of bethanechol chloride as an experimental therapy. The pathologically diagnosed patients with AD (n = 35; mean age, 67 +/- 1.5 yr) were compared with a group of samples from normal age-equivalent autopsied controls (n = 22; mean age, 68 +/- 2 yr) and autopsied AD brains (n = 11; mean age, 73 +/- 2 yr). Samples were assayed for choline acetyltransferase (ChAT), acetylcholinesterase, binding to [3H]quinuclidinyl benzilate as an index of total muscarinic cholinergic binding, and [3H]pirenzepine binding as an index of M1 cholinergic receptor subtype binding. Mean levels of ChAT activity were decreased in the biopsied patients to 36% of age-matched autopsied controls. The loss of ChAT activity correlated significantly with the Mini-Mental State Examination, an index of global cognitive function. Mean ChAT activity in autopsied AD cortex was further decreased compared with controls, indicating continuous decline through the course of the disease. Acetylcholinesterase followed a similar, less dramatic decline. No differences were found in [3H]quinuclidinyl benzilate binding or [3H]pirenzepine binding between biopsied and autopsied controls. Neuritic plaque counts did not correlate with either the Mini-Mental State Examination or ChAT activity in the biopsy specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1976

Drug therapy for postragotomy gastric stasis.

An unusual but well-recognized complication of truncal vagotomy with a drainage procedure is severe gastric stasis (atony). In 6 patients presenting with this problem drug therapy was initiated after mechanical obstruction of the gastric outlet was excluded by radiology. Bethanechol chloride was successful in stimulating gastric peristalsis in all the patients, with consequent improvement of symptoms in 5 out of the 6 subjects. Metoclopramide alone was of no value in starting peristalsis but of pssible benefit once gastric motility had begun.

Adult↗
PubMed1992

Galanin-like innervation of rat submandibular and sublingual salivary glands: origin and effect on acinar cell membranes.

The distribution and source of a galanin-like innervation of rat salivary glands has been examined. Additionally, submandibular and sublingual acinar cell membrane responses to galanin or a cholinergic agonist were studied. Galanin-immunoreactive fibers were observed throughout the submandibular and sublingual glands in association with ducts and acini. A subset of submandibular ganglion cells expresses galanin immunoreactivity. Parasympathectomy resulted in a marked decrease in galanin immunoreactivity in the glands. Sympathectomy resulted in marked reduction of dopamine beta-hydroxylase immunoreactivity with no appreciable change in galanin immunoreactivity. Retrograde labeling experiments demonstrated that galanin-immunoreactive sensory neurons in the trigeminal ganglion do not innervate the submandibular or sublingual gland. These results indicate that the galanin-like innervation of rat salivary glands is derived from parasympathetic nerves to the glands. Since rat sublingual glands contain largely mucous acini while rat submandibular gland acini are seromucous, electrophysiological responses to galanin and the muscarinic agonist, bethanechol, were compared. Agonist-induced voltage shifts varied between the two glands. The galanin-induced response at the level of the resting membrane potential in submandibular acinar cells was a hyperpolarization, while that in sublingual acinar cells was a depolarization. There was also a greater voltage dependence to the galanin-induced submandibular response than to the sublingual response. Differences were also noted in the acinar cell response to cholinergic stimulation between these glands. These results demonstrate the existence of a galanin-like innervation to salivary glands that may be functionally relevant. Moreover, the results challenge the idea that agonist-induced membrane responses are similar among acinar cells of different glands.

Animals↗
PubMed1989

Effect of metoclopramide, bethanechol, and loperamide on gastric residence time, gastric emptying, and mouth-to-cecum transit time.

The effects of metoclopramide, bethanechol, and loperamide on the gastric residence time (GRT), gastric emptying (GE), and mouth-to-cecum transit time (MCTT) of a solution were investigated in three separate studies of five healthy male volunteers each. Metoclopramide in doses of 5, 10, and 15 mg prolonged GRT by 33, 88, and 162%, respectively, almost reaching statistical significance (p 0.058). A relationship was observed between GRT prolongation, and metoclopramide area under the plasma-time curve (p 0.01) and metoclopramide observed time to maximum concentration (p 0.01). Metoclopramide had an inconsistent effect on MCTT. Bethanechol 50 mg prolonged GRT by 64% (p 0.031) and had no effect on MCTT. Loperamide at doses of 2 and 8 mg prolonged GRT by 18 and 115% (p 0.043) and MCTT by 30 and 130% (p 0.0001), respectively. None of these motility-altering agents affected GE.

Adolescent↗
PubMed1992

Bethanechol inhibition of chicken intestinal brush border Na/H exchange: role of protein kinase C and other calcium-dependent processes.

Bethanechol, a muscarinic agonist, inhibits the initial rate of amiloride-sensitive Na uptake by intact mucosa of avian small intestine as well as by isolated chicken villus enterocytes, an effect that is maximal at 90 seconds and reverses by 6 minutes. Bethanechol similarly decreases intracellular pH in isolated cells suspended in bicarbonate-free buffer in a time course similar to inhibition of enterocyte Na uptake, suggesting inhibition of Na/H exchange. In brush border membrane vesicles rapidly prepared from cells stimulated with bethanechol, proton-dependent 22Na uptake is transiently inhibited in a time course similar to inhibition of cell Na uptake. Bethanechol also stimulates transient translocation of protein kinase C from the cytosol to the particulate fraction, a portion of this activity translocating to the brush border membrane. To determine the calcium dependence of bethanechol's action, enterocytes were loaded with varying concentrations of the calcium buffering agent quin-2. Inhibition of cell Na uptake by the calcium ionophore ionomycin could be completely reversed by quin-2 buffering in a concentration-dependent manner. In contrast, quin-2 buffering had little or no effect on the inhibition of Na uptake caused by the protein kinase C activators phorbol esters and oleoylacetylglycerol. Bethanechol's inhibitory effects were partially, but not completely reversed by quin-2 buffering. These data suggest that the effects of bethanechol on chicken villus enterocyte brush border Na/H exchange are mediated by calcium-dependent process(es) as well as by protein kinase C.

Animals↗