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PubMed1992

Role of acetylcholinesterase in airway epithelium-mediated inhibition of acetylcholine-induced contraction of guinea-pig isolated trachea.

To seek evidence for the involvement of acetylcholinesterase activity in the modulatory influence of the airway epithelium, we examined responses to acetylcholine (ACh), bethanechol, histamine or KCl in isolated epithelium-intact and epithelium-denuded guinea-pig trachealis preparations. The concentration-response curves to ACh were shifted 26-fold to the left by epithelial denudation but the contractile response to KCl was not altered. The response to histamine in epithelium-denuded preparations increased 4-fold with no attenuation in the presence of physostigmine (30 nM). Physostigmine (30 nM) potentiated the response to ACh in epithelium-intact tissues more (about 26-fold) than in epithelium-denuded tissues (about 3.5-fold). Thus, in the presence of physostigmine removing the epithelium had only a slight effect (not statistically significant) on the potency of ACh to contract the trachea. Removing the epithelium had no effect on the potency of bethanechol, a muscarinic receptor agonist that is not a substrate for cholinesterases. Physostigmine itself contracted the trachealis muscle but the pD2 values and maximum responses in epithelium-intact and denuded preparations were not significantly different. The frequency-response curves to electrical field-stimulated cholinergic contractions were unaffected by removing the epithelium. In conclusion, the principal mechanism by which the epithelium inhibits contraction of guinea-pig trachea to exogenously applied ACh is via epithelium-derived acetylcholinesterase activity.

Acetylcholine↗
PubMed1993

Opposite modulation by muscarinic M1 and M3 receptors of acetylcholine release from guinea pig ileum as measured directly.

Muscarinic receptor agonist and antagonist effects on acetylcholine release evoked by electrical or dimethylphenylpiperazinium stimulation from guinea pig ileum were evaluated by measuring acetylcholine with a high performance liquid chromatography-electrochemical detector system. AF102B (cis-2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine), a muscarinic M1 receptor agonist, increased markedly the evoked release of acetylcholine. In contrast, pirenzepine decreased the evoked acetylcholine release. 4-DAMP (4-diphenyl-acetoxy-N-methylpiperidine methiodide) and p-F-HHSiD (p-fluoro-hexahydrosiladifenidol), muscarinic M3 antagonists, increased the release of acetylcholine. Atropine enhanced acetylcholine release to a similar extent while bethanechol reduced the electrically evoked acetylcholine release. This reduction was virtually unaffected by methoctramine, but was antagonized by 4-DAMP or p-F-HHSiD. The results from direct determination of acetylcholine suggest that, in contrast to autoinhibition by stimulation of muscarinic M3 receptors, stimulation of presynaptic muscarinic M1 receptors is predominantly involved in enhancement of the acetylcholine release from guinea pig ileal nerves, and that AF102B functions as a muscarinic M1 agonist in this peripheral neuron.

Acetylcholine↗
PubMed1994

Effects of direct and indirect acetylcholine receptor agonists on growth hormone secretion in humans.

Cholinergic pathways in the central nervous system positively influence growth hormone (GH) secretion. In fact pyridostigmine, a cholinesterase inhibitor, enhances both basal and GH-releasing hormone (GHRH)-induced GH secretion while, conversely, pirenzepine, an antagonist of muscarinic M1 receptors, inhibits the GH response to GHRH and to other physiological and pharmacological stimuli. The effect of the cholinergic system on GH secretion probably takes place via inhibition of the release of endogenous somatostatin. In this study in 36 normal adults (26 males and 10 females, age 22-35 years) we compared the effects of three cholinesterase inhibitors (pyridostigmine, 120 mg p.o., n = 19; neostigmine, 10 micrograms/kg i.v., n = 6; physostigmine, 12.5 micrograms/kg i.v., n = 6) and bethanechol, a direct muscarinic receptor agonist that is mainly active on muscarinic M3 receptors (25 micrograms/kg i.v., n = 5), on both basal and GHRH (1 microgram/kg i.v.)-stimulated GH secretion. Pyridostigmine, neostigmine and physostigmine induced a significant GH increase (peak vs. basal levels, mean +/- S.E.: 10.4 +/- 1.6 vs. 0.6 +/- 0.2 micrograms/l, P = 0.0001; 13.3 +/- 1.2 vs. 0.5 +/- 1.1 micrograms/l, P = 0.004; and 14.9 +/- 3.1 vs. 2.7 +/- 1.1 micrograms/l, P = 0.025;, respectively). These drugs also induced a similar potentiation of the GH response to GHRH (peak: 48.3 +/- 5.6 vs. 16.2 +/- 2.2 micrograms/l, P = 0.0001; 49.2 +/- 2.2 vs. 19.9 +/- 5.1 micrograms/l, P = 0.006; and 76.9 +/- 12.4 vs. 18.1 +/- 5.3 micrograms/l, P = 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Muscarinic receptor modulation of glucose-induced electrical activity in mouse pancreatic B-cells.

Acetylcholine (1-10 microM) depolarized the membrane and stimulated glucose-induced bursts of electrical activity in mouse pancreatic B-cells. The acetylcholine effects were mimicked by muscarine while nicotine had no effect on membrane potential. Pirenzepine, an antagonist of the classical M1-type muscarinic receptors, but not gallamine (1-100 microM), an antagonist of the classical M2-type receptors, antagonized the acetylcholine action on glucose-induced electrical activity (IC50 = 0.25 microM). Bethanechol, an agonist of the classical M2-type muscarinic receptors, was approximately 100 times less effective than acetylcholine in stimulating the electrical activity. In addition, acetylcholine (1 microM) induced a marked increase (25%) in input resistance to the B-cell membrane. The results indicate that acetylcholine exerted its effects on the B-cell membrane by inhibiting K+ conductance via activation of a muscarinic receptor subtype distinct from the classical M2-type receptor.

Acetylcholine↗
PubMed1985

Cholinergic effects on gallbladder emptying in humans.

The role of cholinergic mechanisms in the control of gallbladder emptying has not been defined. In this report a scintigraphic technique using 2,6-dimethylphenylcarbamoylmethyl iminodiacetic acid labeled with technetium 99m to visualize the gallbladder and its emptying and diethylenetriamine pentaacetic acid labeled with indium 111 to visualize the stomach and its emptying was used to study 43 normal subjects and 18 patients with vagotomies. Direct cholinergic stimulation with bethanechol induced significant gallbladder emptying. Cholinergic blockade with atropine sulfate decreased the gallbladder emptying responses to a liquid meal, a solid meal, and the infusion of cholecystokinin-octapeptide. In patients with vagotomies, gallbladder emptying was decreased despite accelerated gastric emptying of an ingested liquid meal. The gallbladder emptying response to cholecystokinin-octapeptide was augmented in patients who had undergone vagotomy. These studies suggest that cholinergic receptors may be important in the regulation of human gallbladder emptying.

Adult↗
PubMed1985

Selective inhibition of pentagastrin- and cholecystokinin-stimulated exocrine secretion by proglumide.

The effectiveness and selectivity of proglumide, a putative cholecystokinin/gastrin receptor antagonist in vitro, were examined on gastric acid and pancreatic secretion in vivo. Gastric secretion was measured in conscious dogs in the basal state and during infusion of pentagastrin, histamine, or bethanechol, alone or in combination with proglumide (300 mg/kg . h). Pancreatic secretion was measured in anesthetized rats in response to cholecystokinin-octapeptide or secretin, alone or in combination with proglumide (100 mg/kg). Proglumide inhibited pentagastrin-stimulated secretion but had no effect on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion. Inhibition of pentagastrin-stimulated secretion was of the competitive type. An apparent inhibitory constant was calculated to be 300 mg/kg . h; this dose is capable of eliciting plasma concentrations of approximately 1 mM. This estimate corresponds closely to that derived from measurements in isolated canine parietal cells. Proglumide also inhibited cholecystokinin-stimulated but not secretin-stimulated pancreatic secretion. The lack of effect of proglumide on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion implies that background gastrin has no direct or synergistic influence on stimulation by other secretagogues. The selective effect of gastrin receptor antagonists contrasts with the effectiveness of muscarinic and histamine H2-receptor antagonists against secretion induced by all types of stimulants. Accordingly, the antisecretory potential of gastrin receptor antagonists is confined to digestive secretion when the effect of gastrin is optimal. Their potential as antitrophic agents in duodenal ulcer disease, however, has not been explored yet.

Animals↗
PubMed1986

Gallbladder emptying response to sham feeding in humans.

Cholescintigraphy, using 99mTc-HIDA, was employed to determine the gallbladder emptying response to sham feeding of a steak and potato meal, and to compare it with the emptying responses to direct cholinergic stimulation by bethanechol and to ingestion of the test meal. The maximal cumulative gallbladder emptying response to sham feeding was 44.1% + 10.1%, which was not significantly different from the response to bethanechol. Cholinergic blockade with atropine eliminated the emptying response to sham feeding. Also, sham feeding did not stimulate gallbladder emptying in patients with vagotomy. This study suggests that intact vagus nerves and cholinergic pathways are required in order for the gallbladder to respond to sham feeding. The precise mechanism for this effect has not been elucidated.

Adult↗
PubMed1986

Absent postprandial duodenal motility in a child with cystic fibrosis. Correction of the symptoms and manometric abnormality with cisapride.

A 19-mo-old boy with cystic fibrosis presented with a lifelong history of feeding problems and constipation, and an 8-mo history of episodes of repeated retching, diaphoresis, dehydration, and somnolence after eating. Tests of esophageal motility and gastric emptying of a 5% glucose meal were normal. Antroduodenal pressure recordings during fasting demonstrated the presence of all phases of the interdigestive motor complex. After consumption of a 240-ml complex liquid meal, however, the contractile pattern that generally accompanies eating was absent and gastric emptying was markedly delayed. When bethanechol or metoclopramide was given 10 min before the complex liquid meal, there was a paucity of contractile activity, gastric emptying was slow, and symptoms of lethargy, diaphoresis, and retching were present. When cisapride was given, there was frequent irregular contractile activity, faster gastric emptying, and no symptoms of lethargy. During the past year treatment with cisapride has been a requirement in order to prevent recurrence of the symptoms. Antroduodenal pressure studies proved helpful in the identification of a treatable manometric abnormality that was associated with symptoms of delayed gastric emptying.

Bethanechol↗
PubMed1987

Calcium dependence of neurotensin stimulation of circular colonic muscle of the rabbit.

The effect of neurotensin on smooth muscle contraction was compared in strips from rabbit proximal and distal circular colonic muscle. The effective dose for neurotensin stimulation that caused a 50% response in both tissues was similar (1.3 X 10(-10) M). The maximal isometric stress, however, was greater in the distal colon than in the proximal colon (p less than 0.01). Neurotensin stimulation of both proximal and distal colon was unaffected by tetrodotoxin, phentolamine, propranolol, naloxone, or atropine. Neurotensin-stimulated contraction was inhibited by "Ca2+-free" (pCa = 5.1) or La3+ buffer. Verapamil (10(-6) M) or nitroprusside (10(-4) M) decreased neurotensin stimulation of proximal and distal colon by approximately 40% (p less than 0.05). Removal of Ca2+ from the buffer inhibited stimulation of muscle contraction by high extracellular potassium [( K+]o) more than bethanechol stimulation (p less than 0.01). La3+ (1 mM) inhibited the contraction stimulated by bethanechol or increased [K+]o. Although verapamil inhibited contraction by bethanechol and increased [K+]o by approximately 50%, nitroprusside had no effect on the contraction mediated by these stimulants. 8-Bromo-guanosine 3',5'-cyclic monophosphate (cGMP) inhibited neurotensin, but not [K+]o or bethanechol-stimulated contraction. These data suggest (a) neurotensin stimulated colonic contractions at a concentration that is potentially physiologic, (b) neurotensin stimulated colonic smooth muscle directly without neural mediation, (c) neurotensin stimulation of colonic muscle is controlled by [Ca2+]o and [cGMP]i.

Animals↗
PubMed1987

Influence of vagal integrity on gastrin and somatostatin release in dogs.

Plasma gastrin and somatostatin responses to ingestion of a solid meal, to insulin hypoglycemia, and to intravenous infusion of gastrin-releasing peptide were measured in 4 conscious dogs with and without bilateral cryogenic blockade of the cervical vagus nerves. Vagal cooling to -2 degrees C abolished meal-stimulated rises in plasma gastrin and somatostatin. Atropine did not modify the gastrin response to cooling but bethanechol reduced the magnitude of inhibition to 37% +/- 9% without influencing plasma somatostatin. Gastrin-releasing peptide elevated postprandial plasma gastrin during vagal blockade to levels comparable to those with the vagus intact but did not alter the nadir plasma somatostatin response. The plasma gastrin and somatostatin rises associated with insulin hypoglycemia were similarly inhibited by cooling to -2 degrees C. Cooling to 12 degrees C, which selectively blocks vagal inhibitory pathways, had no effect on meal-stimulated gastrin release and partially decreased the plasma gastrin response to insulin hypoglycemia. Thus, gastrin release by food and by insulin hypoglycemia is mediated by a vagal nonmuscarinic excitatory pathway that is independent of changes in circulating plasma somatostatin but may include participation by the candidate neurotransmitter gastrin-releasing peptide.

Animals↗
PubMed1987

Divergent effects of bombesin and bethanechol on stimulated gastric secretion in duodenal ulcer and in normal men.

To further investigate differences in the responses of normals and patients with duodenal ulcer with respect to gastrin release and acid and pepsin secretion, we infused bombesin (1 microgram/kg X h) or bethanechol (40 micrograms/kg X h) during the middle hour of a 3-h infusion of pentagastrin and compared the results with a pentagastrin infusion without added drug. Pentagastrin dosage (0.1 microgram/kg X h) was set to give about half-maximal response, to detect either inhibition or further stimulation of gastric secretion, whereas the dose of bombesin was chosen to give maximal gastrin but less than maximal acid secretion. Serum gastrin and somatostatin were also measured. In all subjects tested, bethanechol produced no effects on acid, gastrin, or somatostatin release but increased pepsin output. By contrast, bombesin inhibited pentagastrin-stimulated acid output in all 6 normal men by an average of 55%, whereas it inhibited acid output in only 2 of the 9 men with duodenal ulcer. Serum gastrin increases after bombesin in duodenal ulcer were three to four times greater than in normals. Although bombesin stimulates acid only by releasing gastrin, we postulate that bombesin may also simultaneously limit acid and pepsin secretion and speculate that this effect could be mediated by bombesin-induced somatostatin release. The cause for differences between duodenal ulcer and normal remain speculative.

Adult↗
PubMed1987

Properties of the feline pyloric sphincter in vitro.

The purpose of this study was to determine the intrinsic functions of the feline pylorus in vitro. The myoelectric and pressure characteristics of the intact pylorus, antrum, and duodenum, free of extrinsic hormonal or neural influences, were studied in an in vitro bath that allowed separation of the bathing medium surrounding the different bowel segments. Basal recordings revealed a zone of tonic high pressure of 28.4 +/- 3.5 mmHg (mean +/- SEM) at the pylorus. The basal slow wave frequencies in the pylorus and duodenum were 2.8 +/- 1.4 and 12.6 +/- 0.6 cycles/min, respectively. Spontaneous action potential-associated phasic contractions of the pylorus were noted in 38% of preparations. Enteric nerve stimulation with direct electric current (10 Hz, 1 ms, 10-50 V) applied proximal to the pylorus gave relaxation of the pylorus at the lower voltages and rebound excitation at higher voltages. Electrical stimulation distal to the pylorus yielded phasic contractile pyloric response during the entire stimulus. The duodenal instillation of 0.5 N HCl produced action potential-associated phasic contractions of the pylorus and duodenum but not the antrum. Pyloric responses to electrical stimulation or acidification were abolished by tetrodotoxin (10(-5) M). Bethanechol (10(-6) M) or substance P (10(-7) M) produced a contractile response at the site of stimulation but this response was not transmitted to include adjacent bowel segments. These studies suggest that the pyloric sphincter with its intrinsic reflex properties can be studied in vitro.

Action Potentials↗
PubMed1987

Effects of somatostatin on gallbladder emptying.

Because approximately 80% of reported patients with somatostatinomas have gallstones, this study was performed to determine the effects of exogenous somatostatin on gallbladder emptying responses to liquid and solid meals, direct cholinergic stimulation by bethanechol, indirect cholinergic stimulation by sham feeding, and intravenously administered octapeptide of cholecystokinin. Gallbladder emptying was quantitated using 99mTc-HIDA and a gamma-camera on line to a digital computer. Somatostatin, administered at a dosage of 7 micrograms/kg X h, prevented the gallbladder emptying responses to both test meals, sham feeding, and bethanechol. The maximal gallbladder emptying response to octapeptide of cholecystokinin at 5.0 ng/kg X min was reduced from 93.2% +/- 4.8% to 57.1% +/- 9.9% (p less than 0.01) and to octapeptide of cholecystokinin at 0.5 ng/kg X min from 91.3% +/- 5.3% to 14.8% +/- 4.2% (p less than 0.01). These findings suggest that somatostatin is a potent inhibitor of gallbladder emptying in humans. This may be an important factor in the development of gallstones in patients with somatostatinomas.

Adult↗
PubMed1988

Calcitonin gene-related peptides I and II and calcitonin: distinct effects on gastric acid secretion in humans.

The human calcitonin gene-related peptides I and II (CGRP I and CGRP II) are two neuropeptides that have been recognized throughout the gastrointestinal system including the stomach. The present study was undertaken to compare in healthy volunteers the effects of intravenous infusions of CGRP I and CGRP II (79 pmol/kg.h) on pentagastrin-stimulated acid secretion to those of calcitonin (88 pmol/kg.h). Calcitonin gene-related peptide I did not inhibit basal or pentagastrin-stimulated acid secretion. However, CGRP II and calcitonin inhibited pentagastrin-stimulated acid responses by 20% and 28%, respectively (p less than 0.05 and p less than 0.01), whereas basal acid output was only reduced with calcitonin (p less than 0.05). These effects were recognized with low doses of pentagastrin, and absent with high doses suggesting competitive inhibition. Furthermore, step-doses of CGRP I and CGRP II (79-320 pmol/kg.h) were given intravenously on continuous pentagastrin stimulation and compared with calcitonin (88-352 pmol/kg.h). Calcitonin gene-related peptide II and calcitonin induced a dose-dependent decrease of acid output, whereas CGRP I was ineffective. The inhibitory effects of CGRP II and calcitonin are not due to increased gastric alkaline secretion or to somatostatin release, as neither peptide stimulated gastric bicarbonate secretion or induced an increase in circulating somatostatin. In conclusion, CGRP II, unlike CGRP I, inhibits gastric acid secretion in humans. Inhibitory effects of CGRP II and of calcitonin were comparable. The results imply that CGRP I and II, at the level of the stomach, have distinct biological properties in humans.

Adult↗
PubMed1988

Intracerebroventricular pressure inhibits gastric antral and duodenal contractility but not acid secretion in conscious rabbits.

Acute nausea characteristically accompanies head injury or increased intracranial pressure, or both. The etiology of this symptom is unclear. We studied the effect of increased intracranial pressure on gastric antral and duodenal contractility and gastric acid secretion in conscious rabbits. Intracerebroventricular pressure was maintained at 3, 8, or 13 cmH2O using normal saline perfused into the lateral cerebral ventricle and gastric antral and duodenal contractility was monitored using chronically implanted strain gauge force transducers. Gastric acid secretion was measured in a separate group of rabbits with chronically implanted gastric cannulas. Increased intracerebroventricular pressure (13 cmH2O) resulted in an immediate suppression of the amplitude of gastric and duodenal contractions by greater than 80% and greater than 60%, respectively. After normalization of intracerebroventricular pressure, the contractile pattern returned to basal levels. Intravenous bolus injection of bethanechol reversed the suppression of gastric antral contractility induced by increased intracranial pressure. Increased pressure for 2 h did not modify gastric acid output as compared with normal pressure controls, whereas atropine significantly inhibited and histamine stimulated gastric acid secretion in the same animals maintained at normal pressure. These results demonstrate that acutely increased intracranial pressure rapidly and reversibly inhibits gastric and duodenal motor function in conscious rabbits.

Animals↗
PubMed1988

Interactions of aromatic amino acids with gastric secretagogues in humans.

To determine the interactions of phenylalanine and tryptophan with gastric secretagogues, acid secretory studies were performed in 10 healthy subjects. Phenylalanine and tryptophan potentiated the gastric secretory responses following low doses of pentagastrin, whereas their effects on acid secretion stimulated by low doses of histamine or the cholinergic bethanecol were additive. Phenylalanine and tryptophan did not increase maximal acid output stimulated by pentagastrin, histamine, or bethanecol. Doses of the H2-receptor antagonist ranitidine, the prostaglandin E1 analogue misoprostol, atropine, and somatostatin that produced approximately 50% inhibition of pentagastrin-stimulated acid secretion significantly inhibited phenylalanine- and tryptophan-stimulated acid secretion. After the combination of either phenylalanine or tryptophan with pentagastrin, the H2-receptor antagonist significantly inhibited gastric acid secretion, whereas somatostatin, atropine, and the prostaglandin E1 analogue were not effective. These results indicate that both phenylalanine and tryptophan potentiate gastric acid secretion stimulated by a submaximal dose of pentagastrin, whereas their effects on histamine- and bethanecol-stimulated secretion are additive. The potentiating effects of phenylalanine and tryptophan on pentagastrin-stimulated acid secretion depend, at least in part, on intact histamine pathways.

Adult↗