Cholinergic control of gastric acid secretion

Summary In the perfused stomach preparation of the anaesthetized rat the cholinergic agonists acetylcholine (ACh) and bethanechol stimulated gastric acid secretion. Both agonists produced similar maximal acid output (70 mol/15 min) when infused intravenously. However, bethanechol was more potent, eliciting half maximal stimulation at 1.98 mol/kg/h. Secretory responses to either agonist were antagonized in a dose related fashion by blockade of muscarinic receptors with atropine. In contrast, inhibition of nicotinic receptors with hexamethonium produced a striking potentiation of ACh stimulated secretion whilst the bethanechol elicited secretion remained unaffected. In the presence of full nicotinic receptor blockade the ACh response curve was shifted to the left sixfold, half maximal stimulation being produced at 1.79 mol/kg/h. Cimetidine partially inhibited the secretory responses elicited by either ACh or bethanechol while blockade of adrenoceptors ( and ) did not affect acid output induced by cholinergic agonists. Secretion elicited by ACh is interpreted as being the composite effect of prosecretory action and an inhibitory mechanism due to the activation of nicotinic receptors. Hexamethonium, through nicotinic receptor blockade, inhibits the restricting mechanism and thus reveals the full stimulatory action of ACh.     

Role of muscarinic cholinergic mechanisms in the substantia nigra pars reticulata in mediating muscular rigidity in rats

Summary Bethanechol chloride (5–25 g), when injected into the substantia nigra pars reticulata (SNR) of rats, produced muscular rigidity in a dose-dependent way, and in addition, catalepsy and ipsilateral posture. The effects of bethanechol in the dose of 25 g were prevented by coadministration of 10 g scopolamine hydrochloride. Injections of 25 g betanechol or 10 g scopolamine into the reticulata only slightly affected the muscular rigiditiy produced by 15 mg/kg i.p. morphine hydrochloride. The results suggest that muscarinic cholinergic mechanisms in the substantia nigra pars reticulata, although effective by themselves, affect by expression of at least one striatal functional alteration, the muscular rigidity, in a less effective way than GABAergic or endogenous opioid mechanisms do.     

An embryonic chick pancreas organ culture model: characterization and neural control of exocrine release

An embryonic chick (Gallus domesticus) whole-organ pancreas culture system was developed for use as an in vitro model to study cholinergic regulation of exocrine pancreatic function. The culture system was examined for characteristic exocrine function and viability by measuring enzyme release, and noting histological, morphological, and anti-amylase immuno-fluorescence staining changes over a series of incubation times. This embryonic culture system exhibits loss of viability and morphological degeneration after 12 h of incubation time. Characterization and development of this exocrine model system was an important aspect of this study. Assessment of the 18-day-old embryonic chick pancreas model clearly indicated biochemical and cholinergic functionality, and morphological integrity, of the tissue after 4-h incubation. This embryonic age and incubation period were utilized for all subsequent cholinergic studies. The in vitro model was used to study parasympathetic regulation of exocrine function via the muscarinc receptors present in the embryonic chick pancreas. The effects of synthetic muscarinic agonists (bethanechol and carbachol) and subtype-specific antagonists affected amylase release to varying degrees suggesting heterogeneity of receptors. The effects of the muscarinic receptor antagonists atropine (non-specific), pirenzepine (M(1)-selective) and 4-DAMP [4-diphenylacetoxy-N-methyl-piperidine methiodide] (M(3)-selective) on bethanechol-stimulated amylase release were examined. Atropine and 4-DAMP at concentrations of 2 microM and higher significantly inhibited (p<0.05) agonist-stimulated amylase release, while pirenzipine did not at 2 microM, but did at 200 microM. The M(3) subtype selective antagonist 4-DAMP (2 pM-2 mM) significantly inhibited (p<0.05) 5 mM bethanechol-stimulated amylase release at concentrations of 2 microM and greater (amylase activity decreased from 100.61 to 49.41 U/l/mg). The data suggest the existence of a muscarinic receptor subtype for the embryonic chick pancreas exocrine cells characteristic to the mammalian M(3) glandular subtype.     

Hypogammaglobulinaemia and malakoplakia: response to bethanechol

A second patient is described with the syndrome of hypogammaglobulinaemia and malakoplakia; he too responded dramatically to bethanechol treatment and remains well on it.Abbreviations FFP fresh frozen plasma - HIG human immunoglobulin - PAS periodic acid Schiff - PHA phytohemagglutinin - SE patient's initials Dr. W. C. Marshall died October, 1983     

Cholinergic dysfunction in Shy—Drager syndrome: Effect of the parasympathomimetic agent,bethanechol

To determine the frequency, severity and organ distribution of cholinergic dysfunction in the Shy—Drager syndrome, eleven patients were prospectively studied. In addition to documenting adrenergic insufficiency, a battery of twelve tests was employed to assess cholinergic function. Six tests demonstrated pupillary, lacrimal, salivary, urinary bladder, sexual and sudomotor dysfunction in the majority of patients. Cardiac vagal function as studied by the heart rate response to deep breathing, the Valsalva manoeuvre, cold face test, apnoeic facial immersion and atropine test was affected in all patients. Oesophageal motility was abnormal in six patients. Cholinergic dysfunction in patients with the Shy—Drager syndrome was widespread but of variable severity and distribution. Subcutaneous administration of the parasympathomimetic agent bethanechol demonstrated hyperresponsiveness of lacrimal, salivary, oesophageal, bowel, bladder and sudomotor functions. It is suggested that the Shy—Drager syndrome is primarily a preganglionic cholinergic disorder with transsynaptic degeneration accounting for the development of postganglionic cholinergic as well as adrenergic dysfunction.     

Bethanechol-induced increase in hypothalamic estrogen receptor binding in female rats is related to capacity for estrogen-dependent reproductive behavior

Neuroactive agents associated with different neurotransmitter systems can modulate the number of hypothalamic estrogen binding sites. It has been demonstrated previously that the muscarinic cholinergic agonist, bethanechol, administered 30 min prior to in vitro estrogen receptor assays increases the concentration of hypothalamic estrogen binding sites by 30-35% in female rats. Bethanechol was without effect on male hypothalamic preparations. In order to investigate further this sex difference and in an attempt to determine a relationship between the modulation of estrogen binding sites and a sexually differentiated function, bethanechol was given to female rats rendered either anovulatory and capable of displaying lordosis or anovulatory and behaviorally insensitive to estrogen. The results showed that bethanechol significantly increased the number of estrogen binding sites in females capable of displaying lordosis but not in females which did not show this estrogen-dependent behavior. It is possible that the capacity for drug-induced modulation of estrogen binding sites could be related functionally to the ability to display lordosis behavior.     

Age-dependent effect of secretagogues during colonic maturation

Intestinal secretory response is altered during colonic development. The aim of this report was to study the developmental changes of the Ca(2+)- and cAMP-induced regulatory pathways with special attention to the direct and indirect effect of secretagogues on the colonic epithelium. We investigated the effect of bethanechol, 5-hydroxytryptamine (5-HT), and histamine on Cl(-) secretion and stimulation of intracellular Ca(2+) ([Ca(2+)](i)) and cAMP in the distal colon of suckling, weanling and adult rats. In the presence of tetrodotoxin, immature colon of suckling and weanling rats displayed higher potency (EC(50)) of 5-HT to stimulate Cl(-) secretion, whereas the potency of histamine was not changed during development. The potency of bethanechol was reduced during weaning and partially restored in adulthood. 5-HT increased cAMP level similarly in both neonatal and adult colonic crypts, but the adults had higher basal level of cAMP than suckling rats. Also the effect of bethanechol on [Ca(2+)](i) was independent of colonic maturation. The results suggest that colonic Cl(-) secretion displays developmental changes of regulation depending on the non-neural secretagogue-signalling pathway and that these developmental changes seem to be localized somewhere outside colonocytes.     

Galanin activates an inwardly rectifying potassium conductance in mudpuppy atrial myocytes

Galanin- and bethanechol-activated K⁺ currents have been studied in mudpuppy atrial myocytes. The galanin and bethanechol K⁺ currents were time-dependent and inwardly rectifying. In GTPS, the galanin and bethanechol currents were reduced progressively as G-protein gated K⁺ channels became activated. GDPS inhibited agonist-induced outward currents. We conclude that galanin and bethanechol activate the same or a very similar inwardly rectifying K⁺ conductance and that activation of a G protein is required.     

Spinal cholinergic inhibition of the pressor response to muscle activation is mediated by muscarinic, but not nicotinic, receptors

This study examined the influence of spinal muscarinic and nicotinic receptors on the cardiovascular adjustments to skeletal muscle activation in anesthetized cats. Microdialyzing into the L(7) dorsal horn increasing doses of the muscarinic receptor agonist bethanechol, but not the nicotinic receptor antagonist mecamylamine, reduced increases in mean arterial pressure (MAP) and heart rate (HR) during hindlimb contraction or passive stretch. Atropine administration accentuated the cardiovascular responses during contraction, but not during passive stretch. These data indicate that muscarinic, but not nicotinic, receptors at the dorsal horn level blunt the pressor response to muscle activity. Further, the data suggest that the two neural pathways involved in muscle contraction or stretch are anatomically distinct.     

Effect of Serotonin on Bethanechol-Stimulated Gastric Acid Secretion and Gastric Antral Motility in Dogs

The purpose of the present study was to evaluate the effect of serotonin on bethanechol-stimulated gastric acid secretion and antral motility in conscious dogs with gastric fistula. Bethanechol stimulated the acid secretion dose-dependently and maintained the frequency and strength of the antral contractions at a high level. Serotonin inhibited the acid secretion dose-dependently, whereas the antral motility was stimulated. The acid inhibition was blocked by propranolol, and dose-response analysis showed inhibition of a non-competitive type. This study thereby shows that serotonin inhibits bethanechol-stimulated gastric acid secretion similarly to salmefamol (β₂-adrenergic agonist)-that is, dose-dependently and non-competitively. Serotonin has been proposed to be a mediator of the β-adrenergic influence on gastric function in vivo, but the counteracting effect of propranolol and the stimulatory effect of serotonin on motility contradict this hypothesis.