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PubMed1990

Histamine augments colonic secretion in guinea pig distal colon.

We tested the hypothesis that the role of histamine in the control of intestinal secretion is mediated by prostaglandins (PGs). The effects of histamine on ion transport were examined in muscle-stripped sheets of mucosa/submucosa set up in flux chambers. Histamine evoked a transient concentration-dependent increase in short-circuit current (Isc) that was reduced by the Cl- transport inhibitor bumetanide. Histamine also caused the release of PGE2. The Isc response to histamine was reduced by indomethacin and piroxicam, which block PG formation, but not by nordihydroguaiaretic acid, which prevents production of lipoxygenase products. 2-Methylhistamine, but not dimaprit, evoked a concentration-dependent increase in Isc. The Isc response to histamine was reduced by the H1-blocker pyrilamine, but not by the H2-antagonist cimetidine. In addition to its direct effect, histamine augmented the responses of endogenously released neurotransmitters with and without indomethacin and hexamethonium. Tetrodotoxin (TTX) reduced the Isc response to 10(-3) M histamine. In the presence of TTX, exogenous histamine amplified the responses to PGs, vasoactive intestinal polypeptide, 2-chloroadenosine, bethanechol, and carbachol. These results suggest that histamine acts at H1-receptors on cells within the gut to mediate intestinal Cl- secretion in part by releasing PGs and by augmenting the actions of endogenously released neurotransmitters. Our results indicate that histamine has a role in the regulation of colonic transport function.

2-Chloroadenosine↗
PubMed1990

Substance P and CGRP mediate motor response of rabbit colon to capsaicin.

Primary afferent nerve terminals located in the mammalian gut wall may play a role in region-specific modulation of gastrointestinal motility. In the present study, we sought to characterize the effect of neuropeptides released from these afferents by capsaicin (CAP) on contractile activity of smooth muscle from the distal rabbit colon. CAP caused a release of acetylcholine and immunoreactivity for substance P (SP) and calcitonin gene-related peptide (CGRP) from the muscle coat. CAP caused a dose-dependent transient stimulation of longitudinal muscle contractions, followed by prolonged inhibition of spontaneous but not stimulated contractile activity. The initial stimulation was abolished by the SP antagonist spantide and by atropine. The inhibitory effect was reduced by repeated exposure of muscle to CGRP. The effect of CGRP on spontaneous contractions differed between longitudinal and circular muscle. In longitudinal muscle, a stimulation was preceded by a transient inhibition, whereas in circular muscle, only inhibition was seen. Both effects were resistant to tetrodotoxin. Repeated exposure of circular but not longitudinal muscle to CGRP resulted in a disappearance of the peptide's inhibitory effect. Exogenously applied CGRP was only a weak antagonist of contractions stimulated by SP and bethanechol. These findings suggest that in the rabbit colon at least the following two neuropeptides are released from CAP-sensitive nerve fibers: a neurokinin peptide from nerve terminals located within the myenteric plexus and CGRP from terminals probably located within the circular muscle layer.

Acetylcholine↗
PubMed2006

Inhibition of the gastric H+,K+ -ATPase by plectrinone A, a diterpenoid isolated from Plectranthus barbatus Andrews.

This work assessed the mechanism underlying the antisecretory gastric acid effect of Plectranthus barbatus Andrews (Lamiaceae) and active constituents. Popularly known as "false-boldo", this plant is used in Brazilian folk medicine to treat gastrointestinal and hepatic ailments. The plant aqueous extract (AE) and isolated compounds were assayed in vivo in pylorus-ligated mice, and in vitro on acid secretion measured as [(14)C]-aminopyrine ([(14)C]-AP) accumulation in rabbit gastric glands and gastric H(+),K(+)-ATPase preparations. Injected into the duodenal lumen, the AE of the plant leaves (0.5 and 1.0 g/kg) decreased the volume (62 and 76%) and total acidity (23 and 50%) of gastric acid secretion in pylorus-ligated mice. Bioguided purification of the AE yielded an active fraction (IC(50)=24 microg/ml) that inhibited acid secretion in rabbit gastric glands with a potency 10 to 18 times greater than that of the originating extract, on both the basal and stimulated acid secretion by histamine (His) (1 microM) or bethanechol (100 microM). At the same concentrations the gastric H(+),K(+)-ATPase activity was also inhibited. The active constituent was chemically identified as the abietanoid dienedione plectrinone A which reduced the H(+),K(+)-ATPase activity with IC(50)=171 microM. The results indicate that inhibition of the gastric proton pump by this diterpenoid may account for the antisecretory acid effect and reputed anti ulcer activity of Plectranthus barbatus.

Abietanes↗
PubMed1976

Lower esophageal sphincter function in children with and without gastroesophageal reflux.

Resting lower esophageal sphincter (LES) pressure was assessed in infants and children 2 weeks to 12 years of age. There were 62 control subjects and 35 patients with reproducible gastroesophageal reflux (GER) determined radiologically. In control subjects without GER: (1) LES pressure was well developed by 2 weeks of age; (2) in children less than 1 year of age, mean LES pressure (43.3 +/- 2.4 mm Hg) was significantly greater than mean LES pressure (30.6 +/- 2.3 mm Hg) children older than 1 year of age; (3) LES sphincter length increased with age; and (4) bethanechol 0.1 mg per kg subcutaneously caused a rise in LES pressure that increased in magnitude as LES resting pressures increased. In patients with GER: (1) only 16 or 35 children had LES pressures below the normal range for their appropriate age group; (2) LES length was shorter than control values in children beyond 6 months of age; (3) GER usually occurred in the absence of hiatus hernia; (4) clinical improvement was common and in patients with low LES pressure was associated with a rise in LES pressures to normal, even in the presenece of hiatus hernia; and (5) bethanechol caused a change and an absolute rise in LES pressure that were not significantly different from those observed in controls. These results indicate that in infants and children low LES pressure is not the sole determinant of GER, and that pharmacological stimulation of the Les could prove to be a useful adjunct to the medical management of GER.

Child↗
PubMed1977

Gastric secretory and motility studies in chronic chagasic patients.

In Chagas' disease, the degeneration of the nerve cells of the intramural parasympathetic ganglia of the stomach causes a wide range of motor and secretory disturbances of the organ. To assess and to correlate the alterations of these two gastric functions, electromanometric and secretory studies were performed in 22 chagasic patients and in 12 control individuals. The gastric antrum electromanometric records were carried out in basal conditions and under the stimulation of methacholine chloride (Mecholyl). Gastric secretory studies were carried out in two sessions with a Kay's test: in the first, with the test alone; in the second, associated with bethanechol chloride (Urecholine). The chagasic patients were divided into two groups according to their gastric motor response to methacholine. It was concluded that the parasympathetic denervation in Chagas' disease changes both acid and pepsin secretions in the same direction but that as the disease worsens, the responsiveness of pepsin secretion to cholinergic action tends to disappear earlier than that of acid secretion.

Adult↗
PubMed1979

Responses of isolated human internal anal sphincter to drugs and electrical field stimulation.

The effects of drugs and electrical field stimulation on muscle strips from the human internal anal sphincter have been examined to provide information about the receptors and nerves that might be involved in the relaxation of the muscle in vivo. Acetylcholine and bethanechol usually relaxed muscle strips; this effect was abolished by hyoscine and antagonized to a varying degree by tetrodotoxin. Hexamethonium in concentrations sufficient to block relaxations to 1,1-dimethyl-4-phenylpiperazinium iodide or nicotine had no effect on relaxations due to acetylcholine, thereby indicating that acetylcholine was acting on muscarinic receptors. The nerves stimulated by acetylcholine released an unknown transmitter. Both 1,1-dimethyl-4-phenylpiperazinium iodide and nicotine relaxed muscle strips, possibly by releasing an adrenergic neurotransmitter which, because the responses to nicotinic receptor-stimulation were blocked by propranolol, stimulated beta-adrenergic inhibitory receptors. Sphincter muscle was also relaxed by electrical field stimulation of intrinsic nerves; this response was blocked by tetrodotoxin but unaffected by hexamethonium, hyposcine, or propranolol. The nerves responding to electrical field stimulation were therefore post-ganglionic, noncholinergic, and nonadrenergic. Compounds discounted as possible neurotransmitters of the noncholinergic, nonadrenergic inhibitory nerves were prostaglandin E2 and F2 alpha, histamine, 5-hydroxytryptamine, and dopamine. Some evidence allows vasoactive intestinal peptide and adenosine triphosphate to be considered as possible neurotransmitters; this could not be confirmed because selective antagonists are not yet available.

Adenosine Triphosphate↗
PubMed1979

Vocalization response to close-arterial injection of bradykinin and other algesic agents in guinea pigs and its application to quantitative assessment of analgesic agents.

A method for determining the vocalization response to algesic agents in conscious guinea pigs is described. Retrograde injection of small amounts of algesic agents into the femoral artery caused transient but obvious vocalization response in a dose-dependent manner. The vocal sound was converted into electrical signals and the envelope of the sound obtained by a peak detector circuit was recorded on an ink-writing oscillograph. The area of the vocalization response circumscribed by a base line and the envelope tracing of the vocal sound was also recorded. Bradykinin, kallidin, acetylcholine (ACh) and nicotine caused the vocalization response, while substance P, histamine, bethanechol, methacholine, serotonin, kallikrein and prostaglandins E1 and E2 caused no or little response. No detectable tachyphylaxis to bradykinin, ACh and nicotine was observed. The pretreatment with hexamethonium abolished the response induced by ACh or nicotine but not the response induced by bradykinin. These results suggest that the paravascular pain receptor of the femoral artery excited by ACh is nicotinic in character. Subcutaneous injection of morphine, pentazocine, diclofenac and aminopyrine inhibited the vocalization response induced by bradykinin in a dose-dependent manner.

Acetylcholine↗
PubMed1976

Gastroduodenal motor gradients in the dog after pyloroplasty.

Circular muscle contractile activity of the antrum and duodenum and gastric emptying of a liquid test meal were investigated in unanesthetized dogs in which the gastroduodenal junction (GDJ) was altered (Heineke-Mikulicz pyloroplasty). After pyloroplasty, antralization (antral-like contractions occurring in the first portion of the duodenum) was observed during the digestive state. Antralization replaced the normal periods of inhibition that separate periods of duodenal contractions during the interdigestive burst. Bethanechol (0.1 mg/kg sc) and metoclopramide (2.0 mg/kg iv) were capable of stimulating interdigestive contractile activity in the altered GDJ. Pentagastrin (1.0 mug/min iv) produced a differential stimulation on the antrum without appreciably affecting duodenal contractile activity. Pyloroplasty also enhanced the emptying of a 300-ml citrate-fat liquid test meal. An intact hypomuscular segment between the antrum and duodenum is important for normal coordinated contractile activity between the antrum and the duodenum and for the normal gastric emptying of liquids.

Animals↗
PubMed1991

BRL 24924, a 5-hydroxytryptamine type 3 antagonist, and gastric secretion of acid and pepsin in vivo.

BRL 24924, a specific 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, was evaluated for effects on gastric secretion of acid and pepsin and possible influences on the effects of serotonin on gastric secretion. Experiments were carried out in conscious dogs with a gastric fistula during a background stimulation of gastric secretion by continuous infusions of pentagastrin, bethanechol or histamine. During infusion of pentagastrin or histamine, BRL 24924, by itself, influenced gastric secretion with stimulation during a low potent background stimulation and inhibition during a potent background stimulation. A serotonin-counteracting effect of BRL 24924 on gastric secretion was found only during infusion of pentagastrin. The secretory stimulation attained by BRL 24924 could be blocked by atropin suggesting a cholinergic mechanism--5-HT4 receptors? The inhibitory effects on gastric secretion and the serotonin-counteracting effects of BRL 24924 are supposed to be via 5-HT3 receptors.

Animals↗
PubMed1988

Effect of BW 942C, an enkephalinlike pentapeptide, on sodium and chloride transport in the rabbit ileum.

BW 942C is a novel enkephalinlike pentapeptide that has been shown to have antidiarrheal action in model systems. The effect of BW 942C on rabbit ileal electrolyte transport was studied to gain insight into the mechanism of the antidiarrheal action of opiate-like compounds. Multiple effects were observed, differing with the basal state of the tissue. BW 942C increased Na absorption in tissues that were not absorbing in the basal state, whereas it had little effect on Na absorption in tissues that were previously absorbing at moderate to high rates (greater than 1 microEq/h.cm2. It increased Cl absorption and caused a dose-related decrease in short-circuit current in all tissues. This effect was reversed or inhibited by naloxone (10(-5) M), suggesting that it is mediated by opiate receptors. No significant change in residual flux was noted. BW 942C was effective from both the serosal and mucosal side; however, it required a 2-log higher dose on the mucosal side (10(-4) M, maximal) to achieve a response similar to that observed with serosal application (10(-6) M, maximal). The ability of BW 942C to alter stimulated secretion was studied using theophylline, prostaglandin E2, vasoactive intestinal peptide, and bethanechol. There was significantly less Cl secretion in BW 942C-treated tissues than in control tissues after stimulation with prostaglandin E2 (10(-7) M). However, this effect was not apparent at higher doses of prostaglandin E2 and there was no inhibition of the short-circuit current response to any of the secretory stimuli by BW 942C. Loperamide was also found to be unable to inhibit the Cl secretion or change in short-circuit current stimulated by theophylline. Although opiates have been shown to be moderately effective antidiarrheal agents, their ability to influence mucosal electrolyte transport is weak and may only account for part of their antidiarrheal action.

Animals↗
PubMed1976

Metoclopramide stimulates prolactin secretion in man.

Serum prolactin concentrations increased approximately 6-fold after oral or intravenous administration of 10 mg of metoclopramide to adult men. Prolactin remained significantly elevated up to 9 h after oral metoclopramide and for at least 2 h after iv metoclopramide. Bethanechol did not increase serum prolactin, and atropine did not inhibit metoclopramide-induced prolactin elevation, suggesting that the cholinergic-like properties of metoclopramide were not responsible for the observed prolactin responses. Pre-treatment with 500 mg L-dopa inhibited the early metoclopramide-induced prolactin increase, which is consistent with the possibility that metoclopramide acts by inhibiting dopamine-mediated hypothalamic secretion of prolactin inhibitory factor. As a potent stimulus of prolactin release, metoclopramide may be useful in clinical investigation of hypothalamic-pituitary function.

Administration, Oral↗
PubMed1990

Photodynamic action of sulphonated aluminium phthalocyanine (SALPC) on isolated rat pancreatic acini.

The photodynamic action of SALPC has been investigated on dispersed, perifused, acini isolated from the rat pancreas. Stimulation of secretion was assessed by measuring amylase release and membrane permeabilization determined by the leakage of cytoplasmic lactate dehydrogenase (LDH) and by the efflux of 86Rb from preloaded acini. Light alone (greater than 570 nm, less than or equal to 18,400 lux), or SALPC (less than or equal to 1 microM) in the absence of light, had no effect on pancreatic acini but cellularly bound SALPC when illuminated caused a dose-dependent, light intensity-dependent and temperature-dependent release of amylase. Singlet oxygen generated by photon-activation of SALPC was measured by the formation of an imidazole adduct and bleaching of the secondary substrate, RNO. Whereas illumination caused a rapid increase in photodynamically-evoked pancreatic amylase release, the efflux of 86Rb and loss of cytosolic LDH were markedly delayed in onset: similar results were obtained with monochromatic laser light (633 nm). In contrast, the muscarinic agonist bethanechol evoked a rapid increase in amylase release but with an almost immediate efflux of 86Rb. Finally, electron microscopy confirmed that the structural integrity of the pancreatic acinar cells was maintained after the photodynamic action of SALPC. It is concluded that the stimulation of amylase secretion and membrane permeabilization by SALPC is due to the generation of singlet oxygen. However, the consistent difference between the time course of amylase secretion and membrane permeabilization makes it likely that an initial stage in photodynamic drug action involves oxidation of plasma membrane protein and activation of secretagogue receptors or the G-proteins and their effector systems.

Amylases↗
PubMed1989

Local effect of substance P on colonic motor activity in different experimental states.

We studied the effects of close intra-arterial injections of substance P on colonic motor activity in the conscious state, during anesthesia, and during acute laparotomy. In the conscious state, with enteric nerves intact, substance P stimulated postsynaptic cholinergic neurons to induce a large amplitude and long duration contraction. This response was blocked by prior close intra-arterial injection of atropine and tetrodotoxin (TTX) but not hexamethonium. Hexamethonium and TTX given alone, close intra-arterially, induced a series of short-duration contractions. Prior close intra-arterial administration of hexamethonium significantly enhanced the colonic motor response to substance P. After blockade of nerve conduction by TTX, substance P induced a series of short-duration contractions with characteristics different from those when the nerves were functioning. Anesthesia alone had little effect on the colonic motor response to substance P, but laparotomy inhibited it significantly. Laparotomy similarly inhibited the contractile response to bethanechol. Gut handling had no further effect on this inhibition. We conclude that in the conscious state substance P acts preferentially on postsynaptic cholinergic neurons to contract colonic circular muscle. When the intrinsic nerves are blocked, substance P may act directly on the smooth muscle to induce circular muscle contractions with characteristics different from those induced when nerves are intact. Substance P also has a weak inhibitory motor effect by its action on presynaptic neurons that synapse on postganglionic intrinsic inhibitory neurons. Anesthetic doses of barbiturates have no major effects on the neuromuscular response to substance P, but laparotomy significantly inhibits the smooth muscle response and selectively blocks some neurons.

Animals↗
PubMed1985

Gastroduodenal motility disturbances in man.

The specialised regions of the stomach include the cardia, fundus, body, antrum and the pylorus. Not only do these regions have specific secretory functions, but also, they have specific motor functions as well. For example, the proximal stomach is most important in regulating emptying of liquids and the distal stomach and pylorus, the emptying of solids. Disorders of gastric emptying can be classified into two major categories: mechanical obstruction due to increased resistance and functional obstruction (gastroparesis) due to pump failure. Gastroparesis is best diagnosed using a solid test meal which is labelled by a gamma-emitting radionuclide. Agents employed to treat gastroparesis include bethanechol, metoclopramide and domperidone. Entero-gastric reflux occurs when there are abnormalities in the duodeno-gastric pressure gradient or the duodeno-gastric resistance mechanism. Excessive entero-gastric reflux may be seen in patients with gastric ulcers, chronic obstructive pulmonary disease, post-cholecystectomy syndrome or post-operative entero-gastric reflux gastritis. The diagnosis of entero-gastric reflux gastritis depends upon typical symptoms and the demonstration of excessive entero-gastric reflux by scintigraphic techniques or the measurement of bile concentrations within the stomach. Medical treatment with bile chelating agents and surface coating agents has been disappointing. Surgical treatment should only be undertaken as a last resort.

Diet↗
PubMed1961

Effects of drugs on partially and completely denervated skeletal muscle of the frog.

The sensitivity of completely denervated and the innervated end-plate regions of partially denervated frog's sartorius muscles to stimulation by drugs has been investigated. The drugs were tested on muscles isolated 12 to 39 days following denervation. On the basis of the results obtained most of the drugs could be put into one of two main groups. The first group included choline, tetramethylammonium, carbachol and decamethonium; these drugs readily stimulated non-denervated muscles, and chronic denervation, either partial or complete, greatly increased the sensitivity of the muscles. The second group included pilocarpine and carbamate of (2-hydroxypropyl) trimethyl ammonium chloride (Bethanechol, U.S.P.). The muscles were relatively insensitive to stimulation by these two drugs. They could stimulate the muscles if applied in high enough concentrations, but the responses thus obtained could not be distinguished from responses produced by similar concentrations of sucrose and chronic denervation did not increase the sensitivity of the muscles to stimulation by these two drugs. Methacholine, like the drugs in the second group, was unable to stimulate the muscles in low concentrations, but chronic denervation rendered the muscles sensitive to stimulation by this drug. Tetraethylammonium presented a completely different pattern of activity which was consistent with a hypothesis that in low doses this drug stimulates skeletal muscle by causing a release of acetylcholine from nerve endings in the muscle.

Acetylcholine↗
PubMed1992

Actions of cholinergic agonists and antagonists on the efferent synapse in the frog sacculus.

Intracellular recordings were made from hair cells in the frog saccular epithelium isolated with its innervating nerves. Inhibitory post-synaptic potentials (IPSPs) were recorded from hair cells when the efferent fibers were activated by electrical stimulation. The effects of acetylcholine (ACh), cholinomimetics, and cholinergic antagonists on the efferent synapse were studied in a preparation where the IPSPs can be observed directly. ACh or carbachol (CCh) produced a transient membrane hyperpolarization with a decrease in input resistance followed by an abolition or reduction of the IPSP. In a low Ca2+ medium where efferent synaptic activity was abolished, ACh or CCh still induced hyperpolarization, though the response appeared to be smaller than that in normal medium. Neither nicotinic (dimethyl-4-phenyl-piperazinium (DMPP), phenyltrimethylammonium (PTMA) and nicotine) nor muscarinic (muscarine, methacholine, bethanechol and oxotremorine) agonists induced the membrane hyperpolarization, but the former drugs inhibited the IPSPs while the latter drugs did not. Both d-tubocurarine and atropine inhibited the IPSP, but the d-tubocurarine was more potent, causing inhibition even at a dose of 0.5 microM while 2 microM or more atropine was needed. The ACh- or CCh-induced hyperpolarization was inhibited completely by d-tubocurarine (5 microM), but only slightly by atropine (5 microM). These results may indicate that the IPSP and the effects of ACh or CCh are based on a direct interaction between ACh or CCh and ACh receptors on the hair cells.

Acetylcholine↗
PubMed1990

Characterization of the neurons of the mouse hypogastric ganglion: morphology and electrophysiology.

The somata of mouse hypogastric ganglion cells injected with Lucifer yellow were ovoid in shape, lacked dendritic processes but gave rise to a single axonal process. Antidromic activation demonstrated that some of the cells contained in this ganglion innervated the vas deferens. The passive and active membrane properties of the ganglion cells were determined in current clamp experiments. Cells fired tetrodotoxin-sensitive action potentials in response to intracellularly-applied depolarizing current. In voltage clamp evidence was obtained for both a persistent inward calcium current at potentials between -30 and -40 mV and a transient calcium current evoked by step depolarizations to around -20 mV. In current clamp, however, cells did not fire calcium action potentials in the presence of tetrodotoxin. Three potassium currents, IM (blocked by 1 mM barium and by 30 microM bethanechol), IA (blocked by 2 mM 4-aminopyridine) and IK(Ca) fast (blocked by 100 microM cadmium and by 5 mM tetraethylammonium) were characterized in these neurons. In addition, IK(Ca) slow was observed in a small proportion of cells. Fast, all-or-nothing, excitatory synaptic potentials were recorded in response to single stimuli applied to the afferent fibres running to the ganglion. In most cells the excitatory synaptic potentials were suprathreshold for action potential initiation and were markedly reduced or abolished by 100 microM mecamylamine, 1 mM hexamethonium and following desensitization to 100 microM nicotine. Excitatory synaptic potentials arose from stimulation of a single presynaptic nerve process and are typical of strong synaptic inputs.

Action Potentials↗
PubMed1992

Anti-ulcer activity of a slow-release zinc complex, zinc monoglycerolate (Glyzinc).

A slow-release zinc complex, zinc monoglycerolate (ZMG) was examined for its potential gastroprotective activity in various gastric ulcer models. These models comprised (a) oral or parenteral non-steroidal anti-inflammatory drugs (NSAIDs) given to rats whose gastrointestinal mucosa was pre-sensitized by prior development of arthritis, oleyl alcohol-induced inflammation and cold exposure, (b) oral ethanol (12.5-100%) with and without added 4% HCl, (c) intraperitoneal reserpine (5 mg kg-1) in arthritic and normal rats and in normal mice, (d) oral NSAIDs given to mice in which acid and pepsin production was stimulated by co-administration of intraperitoneal bethanechol chloride (5 mg kg-1) to enhance ulcer development, and (e) NSAIDs given to carrageenan-inflamed rats to determine effects of ZMG on paw inflammation. In these models, ZMG given orally was effective in preventing development of gastric lesions, except with propionic acid NSAIDs; the effective doses being apparently dependent on the severity of the mucosal injury. In many of the models ZMG was superior to zinc sulphate and other zinc salts or metal ion complexes investigated but was slightly more effective or equipotent compared with zinc acexamate. ZMG did not impair the anti-oedemic effects of NSAIDs. ZMG is thus an effective agent in preventing ulcer development in a wide range of model systems and may be more effective than zinc salts because of the controlled slow-release of zinc from the complex.

Animals↗