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PubMed1990

Chronotropic response of spontaneously beating mouse atria to various concentrations of glucose.

The effect of different concentrations of glucose on the chronotropic activity of isolated mouse atrial preparations was studied. It was found that glucose in the concentrations from 2.2 X 10(-2)M to 8.8 X 10(-2)M was ineffective to change the chronotropic activity of isolated mouse atria. Moroever, the effects of bethanechol and norepinephrine on the chronotropic activity of isolated atria were not modified in the presence of 8.8 X 10(-2)M glucose. However, it was observed that the presence of high glucose did in fact reduce the contraction amplitude, and in the presence of 8.8 X 10(-2)M, glucose, the contraction amplitude was reduced to almost 50% of its initial contraction amplitude in the bathing medium containing 1.1 X 10(-2)M glucose. Possibility to explain such phenomenon is discussed.

Animals↗
PubMed1990

Characterization of alkaline response induced by cholinergic agents in the rat duodenum: involvement of M2 receptors and the calcium-dependent process.

Duodenal pH, potential difference and acid-neutralizing capacity (HCO3- output) were measured in anesthetized rats, in an attempt to characterize these responses induced by cholinergic agents. When the proximal duodenum (1.7 cm) was perfused at a flow rate of 1 ml/min with saline adjusted to pH 4.5, the pH, potential difference and HCO3- output were 5.2 to 5.5, -3 to -5 mV (mucosa negative) and 1.5 to 1.8 muEq/10 min, respectively. Both carbachol (4 micrograms/kg, i.v.) and bethanechol (100 micrograms/kg, i.v.) significantly elevated all these parameters at the doses that stimulated gastric acid secretion; the net HCO3- output caused by these agents was about 35% of that produced by prostaglandin E2 (300 micrograms/kg, i.v.). These responses induced by carbachol were significantly inhibited by pretreatment with verapamil (0.2 mg/kg, i.v.), a Ca channel blocker, and atropine (0.1 mg/kg, i.v.), a nonselective M1 and M2 antagonist, while they remained unaltered in the presence of pirenzepine (1 mg/kg, i.v.), a selective M1 antagonist, or indomethacin (5 mg/kg, s.c.). However, the effects of prostaglandin E2 on duodenal pH, potential difference and HCO3- output were not significantly affected by any of these agents. These results suggest that the cholinergic agents stimulate HCO3- output in the duodenum, probably mediated by M2 receptors and through the Ca-dependent and electrogenic processes. Endogenous prostaglandins may not be involved in this mechanism.

Animals↗
PubMed1990

Gastric emptying in gastroesophageal reflux and the therapeutic role of prokinetic agents.

The author discusses the role of prokinetic agents, such as bethanechol, metoclopramide, domperidone, and cisipride in the management of gastroesophageal reflux disease. These agents address the upper gastrointestinal motility disturbances that contribute to this disease and therefore have an important role in the acute and long-term medical management of reflux esophagitis.

Bethanechol↗
PubMed1990

Bethanechol induced contraction in mouse spleen.

Bethanechol was shown to induce contraction in mouse spleen. The possibility of initiating such response by stimulating solely muscarinic receptors was tested in isolated spleens from mice. The present data showed that bethanechol was able to further increase the maximum splenic contraction induced by phenylephrine, suggesting that the bethanechol induced contraction was possibly unrelated to stimulating adrenergic receptors. Moreover, clonidine which was able to suppress the phenylephrine induced splenic contraction, was unable to suppress the splenic contraction induced by bethanechol, and this result supported the above notion. These data suggest that the bethanechol induced splenic contraction could be the result of a direct stimulation of muscarinic receptors in mouse spleens, and an indirect effect mediated through the stimulation by bethanechol of sympathetic neurotransmitter release from sympathetic varicosities seems unlikely.

Animals↗
PubMed1990

[Clinical evaluation of bunazosin hydrochloride for the treatment of voiding disturbances due to neurogenic bladder--a double-blind study].

The therapeutic utility of bunazosin hydrochloride was evaluated by a multi-center (67 hospitals) double-blind controlled study in patients who complained of voiding disturbances due to neurogenic bladder. For means of comparison, bethanechol chloride and placebo were used as reference drugs. Bunazosin hydrochloride was orally administered 1.5 mg per day for the first week and 3.0 mg per day for two weeks thereafter (Group E). Bethanechol chloride 15 mg (Group B) and placebo (Group P) were orally administered three times daily for three weeks. Three hundred and twenty-three cases were subjected to this study. The global improvement rating was analyzed for 244 cases (83 in Group E, 78 in Group B and 83 in Group P). The global utility rating (GUR) was analyzed for 252 cases (84 in Group E, 81 in Group B and 87 in Group P). Three hundred and twenty cases (107 in Group E, 104 in Group B and 109 in Group P) were analyzed with respect to overall safety rating (OSR). The global improvement ratings (excellent and good) were 32.5% in Group E, 28.2% in Group B and 21.2% in Group P. In the evaluation of GUR, Group E was superior to Group P. In addition, the incidence judged to be useless in Group E was significantly lower than that in Group B. There were no differences in OSR among these three groups. In the total evaluation of the subjective symptoms, the rates of improvement were not different among these three groups. In the total evaluation of the objective findings, the improvement rate in Group E was significantly higher than that in Group P. In addition, the deterioration rate in Group E was significantly lower than that in Group B. In objective findings before and after administration of bunazosin hydrochloride (Group E), the volume of residual urine, the rate of residual urine and the average flow rate improved significantly However, the bladder capacity, the maximum resting bladder pressure and the maximum urethral pressure did not change significantly. Bunazosin hydrochloride improved the objective findings regardless of the bladder capacity and the maximum resting bladder pressure. These significant improvements were marked in the neurogenic bladder patients who were able to urinate and in the patients whose urethral pressure was high. There were no differences in the incidence of side effects or in the appearance of abnormal values of laboratory findings in these three groups. Neither specific signs nor serious clinical side effects except those reported previously were observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1990

[Efficacy of combination of Ea-0643 (bunazosin hydrochloride) and bethanechol chloride in patients with neurogenic bladder].

Bethanechol chloride, a cholinergic agent and bunazosin hydrochloride, an alpha adrenergic blocking agent were administered orally to 28 patients with neurogenic bladder due to peripheral nerve disorders. To compare the effect of the two drugs, one of the drugs was initially administered orally for 2 weeks, and then both of them were administered for the next 2 weeks. Since there were some significant differences in the patient background between the two groups, it was difficult to compare the two drugs. However combined use of these drugs resulted in both objective and subjective good responses in those patients.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

The current status of gastric prokinetic drugs.

Several current gastrokinetic drugs (metoclopramide, domperidone, cisapride) are analysed in this review. After comparing the pharmacokinetics, the gastrointestinal prokinetic mechanisms and the side effects of each drug, their therapeutic uses are reviewed. All drugs improve symptoms of patients with gastro-oesophageal reflux disease, diabetic gastroparesis and idiopathic gastroparesis, but only cisapride seems capable to maintain a gastrokinetic effect under chronic administration. Erythromycin, which has a dramatic effect on hypomotility in diabetic gastroparesis, and opioid antagonists, may constitute new groups of efficient prokinetic drugs.

Bethanechol↗
PubMed1991

Low dose verapamil and nitroprusside distinguish tonic from cholinergic-induced contractions in in vivo feline lower esophageal sphincter.

Although in vitro studies suggest that cholinergic induced contractions and spontaneous tone are mediated by two different cellular pathways, this has not been shown in vivo. The purpose of this study was to distinguish these types of contractions in the feline lower esophageal sphincter (LES) through use of i.v. selective pharmacologic antagonists. Continuous infusion of the calcium channel antagonist verapamil (16-128 micrograms/kg/min) caused a dose-dependent inhibition of bethanechol induced and tonic pressure change. At 32.0 micrograms/kg/min, verapamil produced significantly greater inhibition of bethanechol induced contractions when compared with inhibition of basal LES tone (57.4 versus 4.8%, P less than .02, n = 5). Verapamil also caused a parallel decrease in LES spike activity associated with bethanechol induced contractions. In contrast, lower doses of nitroprusside (0.5 micrograms/kg/min) inhibited LES tone by over 50% (50.6 +/- 21.8%) yet had no significant effect (16.8 +/- 23.4%) on bethanechol induced contractions. Also, inhibition of basal LES tone correlated poorly with its effect on associated spike activity. It is concluded that in the in vivo feline LES, spike dependent cholinergic contractions can be distinguished from LES tone by the use of low dose verapamil and nitroprusside, respectively. This selective inhibition suggests that two cellular mechanisms mediate LES contractions and that these pathways can be distinguished pharmacologically in vivo.

Animals↗
PubMed1977

Adrenergic regulation of phosphorolysis and hydrolysis of glycogen in smooth muscle of rabbit stomach in situ.

In smooth muscle of rabbit stomachs, activities of hydrolytic and phosphorolytic enzymes of glycogen degradation under the influence of agents stimulating and blocking adrenergic alpha and beta-receptors were studied. The results indicate that beta-adrenergic receptor in smooth muscle activated not only phosphorolytic, but also hydrolytic degradation of glycogen, and the alpha-adrenergic receptor only inhibited phosphorolysis but had no influence on hydrolysis of glycogen.

Acetylcholine↗
PubMed1978

Role of microtubules in granulocyte adherence.

The adherence of human polymorphonuclear leukocytes (PMN) to nylon fibers is inhibited in a dose-dependent fashion by exposure in vitro of these cells to either colchicine or VM-26, both of which agents prevent microtubule assembly. Mean adherence of human PMN was 48% +/- 2%, following treatment with 10(-5) M colchicine or 10(-4) M VM-26 it was reduced to 31% +/- 2% and 7%, respectively. Peritoneal PMN obtained from mice and mink with Chediak-Higashi syndrome (CHS) thought to have a microtubule-membrane disorder affecting the PMN had a mean adherence of 29% +/- 3% and 40% +/- 8% compared to control values of 46% +/- 5% and 73% +/- 8%, respectively, from the mice and mink. Both ascorbic acid and bethanechol, shown previously to enhance microtubule assembly in humans with CHS, normalized granulocyte adherence in PMN obtained from mice with CHS. Cyclic nucleotide levels were not altered by treatment of human PMN with colchicine, nor did they differ between normal and CHS animals. Thus it appears that the state of microtubule assembly may directly affect the properties of the PMN plasma membrane without requiring alterations of cyclic nucleotides as an intermediary.

Animals↗
PubMed1978

Effects of secretagogues and theophylline on canine gastric mucosal cyclic nucleotides.

cAMP and cGMP concentrations were measured in gastric mucosa in 18 anesthetized mongrel dogs receiving infusions of histamine (16 microgram/kg/hr), pentagastrin (6 microgram/kg/hr), bethanechol (10 microgram/kg/min), and theophylline (150 mg bolus, then 10 mg/min). The possible synergistic effect of continuous theophylline infusion with the secretagogues was studied in 15 other acute experiments. Antral and fundic mucosa were biopsied and measured by radioimmunoassay for cyclic nucleotides. All the secretagogues did not significantly change antral or fundic mucosal cyclic nucleotide concentrations compared to basal levels. In contrast, phosphodiesterase inhibition by theophylline significantly increased cAMP 11-fold and cGMP threefold in both antrum and fundus. Concomitant infusion of each secretagogue with theophylline did not potentiate the mucosal nucleotide response compared to theophylline alone. In a separate series of 19 experiments in three anesthetized dogs with vagally denervated fundic (Heidenhain) pouches, all the secretagogues which were infused in the same doses as in the acute biopsy studies produced maximal acid secretory responses. Theophylline, on the other hand, failed to stimulate acid secretion in five Heidenhain pouch experiments. These studies fail to implicate cyclic nucleotides as mediators of stimulated canine gastric acid secretion.

Animals↗
PubMed1979

Evidence of reflexive beta adrenergic motor stimulation in the canine stomach and small intestine.

Studies in our laboratory have confirmed the previous observations that adequate electrical stimulation of either the left or right central vagus nerves in the dog after bilateral vagectomy produces relaxation of the stomach and small intestine. On the other hand, central vagal stimuli delivered to dogs that were either chronically reserpinized or were premedicated with the alpha adrenolytic phenoxybenzamine resulted in increased segmenting activity of these two organs. These excitatory responses were abolished by bilateral section of the sympathetic chains and could be reproduced by electrically stimulating the chains. The excitatory effects of either central vagal stimulation, peripheral sympathetic stimulation or intravenous isoproterenol administration could be abolished by dichloroisoproterenol. It was also determined that isoproterenol produced a tonic contraction of the separated muscularis mucosa which was distinguishable from a relaxation of the muscularis externa. It is suggested that a sympathetic pathway exists which is excitatory to the stomach and small intestine and that these excitatory effects are mediated by beta adrenergic neurotransmitters. The results further suggests that the beta excitatory reflex response is mediated by the muscularis mucosa as the target effector system.

Animals↗
PubMed1990

[Pharmacologic effects and safety profile of bethanechol in the differential diagnosis of pseudo-anginal thoracic pain].

The use of bethanecol has recently been proposed to improve the diagnostic accuracy of esophageal manometry in identifying the origin of symptoms in patients with non cardiac chest pain. In this study we report our experience in 30 patients who underwent esophageal functional studies. Despite its low diagnostic value, bethanecol test (two subsequential doses of 50 micrograms/kg) demonstrated an excellent safety profile, there were few side effects, and patients tolerance was good. The Holter electrocardiographic study showed an isolated case of transient atrioventricular block.

Aged↗
PubMed1979

Nicotinic, muscarinic and adrenergic receptors in a parasympathetic ganglion.

Transmission in submandibular ganglia of hamsters was blocked by hexamethonium and dimethylphenylpiperazinium. Dimethylphenylpiperazinium caused depolarization and decreased membrane resistance (Rm). The muscarinic agonist, bethanechol (BCh) caused depolarization of some cells and hyperpolarization of others. Regardless of the change in membrane potential, BCh always increased Rm. Since the responses to BCh persisted in the absence of [Ca++]0, it was concluded that BCh acted directly on the ganglion cells and did not depend upon a transsynaptic process. All responses to BCh were prevented by atropine. The evidence suggests that the ganglion cells possess muscarinic receptors. Like BCh, norepinephrine (NE) either depolarized or hyperpolarized the ganglion cells. There was no relationship between the blockade of transmission by NE and the effect of NE on the membrane potential. The responses to NE were prevented by dihydroergotamine, suggesting the presence of alpha adrenergic receptors on the ganglion cells.

Acetylcholine↗
PubMed1979

Acid secretion and mucosal cyclic nucleotide content of the guinea pig isolated stomach during bethanechol stimulation.

Acid secretion and mucosal cyclic AMP and cyclic GMP content of guinea pig isolated stomach preparations were measured at various times after stimulation with bethanechol (1.7 X 10(-5) M). Significant increases in acid secretion were observed without changes in cyclic nucleotides. Pre-incubation of the tissues with theophylline (10(-3) M) increased acid secretion and nucleotide content. An additional increase in acid secretion was then obtained with bethanechol in these tissues but without further change in nucleotides. Carbachol (30 micrograms/kg) administered by interperitoneal injection to conscious guinea pigs also failed to change gastric mucosal cyclic nucleotides when the animals were sacrificed 15 min later. These results are discussed in relation to the mechanisms of cholinergic stimulation of gastric acid secretion.

Animals↗
PubMed1990

Stimulation of duodenal muscle contraction by porcine or canine motilin in the dog in vivo.

Motilin is a 22 amino acid polypeptide stimulating intestinal muscle contraction. Structure analysis of motilin purified from hog and from dog intestinal mucosa reveals different amino acids in positions 7, 8, 12, 13, and 14. Previous in vitro experiments suggested this species-related structural heterogeneity could generate different bioactive characteristics for these two peptides. This study was designed to compare the stimulatory mechanism of canine and porcine motilins on dog duodenal motility in vivo, testing the hypothesis that canine motilin stimulates a receptor located on the intestinal muscle, while porcine motilin is acting on intrinsic nerves regulating intestinal muscle contraction. Synthetic porcine and canine motilins were administered through a catheter inserted in the caudal pancreatic duodenal artery to stimulate the contraction of a close irrigated duodenal segment. In acute experiments performed on anaesthetized animals, both peptides induced a similar motor stimulation that was inhibited by tetrodotoxin and atropine. In experiments in conscious animals, canine and porcine motilins were equally potent in inducing premature phase III of the migrating motor complex, and the action of both peptides was abolished by atropine or hexamethonium. This study reveals that the structural heterogeneity between porcine and canine motilin does not influence the bioactivity of both peptides in the dog in vivo and suggests that circulating endogenous motilin stimulates intestinal muscle contraction through intrinsic excitatory nerves.

Anesthesia↗