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PubMed1992

Muscarinic regulation of somatostatin release from primary cultures of human antral epithelial cells.

A newly developed, primary culture of human antral epithelial cells has been utilized to examine the effect of parasympathomimetics on somatostatin release. The cholinergic agonists, carbachol and methacholine, stimulated somatostatin secretion in a concentration-dependent manner. Maximal release in response to carbachol was observed at 0.1 mmol/l. Methacholine was 10 times more potent with a significant release being observed at 1 mumol/l, maximal secretion was observed at 10 mumol/l. Somatostatin release, stimulated by the mixed nicotinic and muscarinic agonist, carbachol, was attenuated by the addition of atropine at 0.1 mumol/l but was unaffected by the same concentration of pirenzepine. Methacholine-stimulated release was attenuated by addition of 0.1 mumol/l atropine and unaffected by the same concentration of pirenzepine. The response to methacholine was reversed by the addition of 0.1 mumol/l 4-diphenylacetoxy-n-methylpiperidine methiodide (4-DAMP) and attenuated by 1 nmol/l 4-DAMP indicating that the effect was mediated by an M3 receptor. In conclusion, human antral D cells are stimulated by parasympathomimetics acting at an M3 receptor.

Adult↗
PubMed2002

Oral pilocarpine: new preparation. Xerostomia after radiation therapy: moderately effective but costly.

(1) Dry mouth (xerostomia) is a frequent complication of radiation therapy for cancers of the ear nose and throat. Local measures such as saliva substitutes and anetholtrithione are either moderately effective, inadequately evaluated or little better than placebo. (2) Marketing authorization has been granted in France for an oral formulation of pilocarpine, an old parasympathomimetic agent, in the treatment of radiotherapy-induced xerostomia. (3) According to the results of two double-blind trials, pilocarpine (15-30 mg/day) improves symptoms in about 50 % of patients, compared to improvement in 25% of patients taking placebo. The drug is slow to take effect and has little impact on daily life. It is not known whether pilocarpine helps prevent the complications of xerostomia. (4) Most adverse effects of pilocarpine are due to its parasympathomimetic effects, such as sweating, urinary frequency, flushing, rhinitis and nausea. Pilocarpine must therefore be used with caution in patients with asthma, cardiac arrhythmia, iridocyclitis, and closed-angle glaucoma. (5) In France, this pilocarpine formulation costs 18 times more than a preparation of pilocarpine 2% eye drops used orally (off licence). (6) In practice, patients needing symptomatic treatment of xerostomia after radiotherapy may benefit from oral pilocarpine but, given its limited efficacy and its adverse effects, other local treatments should be tried first.

Administration, Oral↗
PubMed2006

Effect of galantamine on acetylcholinesterase and butyrylcholinesterase activities in the presence of L-carnitine in rat selected brain and peripheral tissues.

OBJECTIVES: The alkaloid galantamine (GAL), which exhibits a combined anticholinesterase and direct parasympathomimetic mechanism of action, is employed in conjunction with therapeutic interventions in the stimulation of central cholinergic transfer in cognitive diseases. We attempted to achieve pharmacologically-induced enhancement of the parasympathomimetic activity of GAL in the key areas of rat brain, using an interactive combination of the alkaloid with the transmembrane enhancer L-carnitine (CAR). METHODS: We investigated activities of acetylcholinesterase (AChE) in brain areas (frontal cortex, basal ganglia, septum and hippocampus) and the hypophysis, and that of butyrylcholinesterase (BuChE) in plasma and liver. RESULTS: Following administration of the highest of the GAL doses used (2.5; 5; 10 mg/kg i.m.), AChE activity decreased mainly in the frontal cortex, hippocampus and hypophysis. In the interaction of GAL and CAR, AChE inhibition was stronger but without any statistical significance. The peripheral inhibition of BuChE was found to be dose-dependent. Premedication by CAR led to a slight change in the values of the activities monitored. CONCLUSIONS: CAR in terms of positive modulation of GAL targeting to the central nervous system had no statistically significant effect.

Acetylcholinesterase↗
PubMed1977

Possibilities for a cholinergic action on smooth musculature and on sympathetic axons in brain vessels mediated by muscarinic and nicotinic receptors.

A pharmacological identification and characterization of cholinergic receptors was carried out in pial arteries of cats. In one series of experiments, the middle cerebral artery was suspended in an organ bath for recording fo circular motor activity. Parasympathomimetic compounds produced either a relaxation or a contraction. The relaxation occurred at low doses (up to 10(-6) M), and the response was inhibited in a competitive manner by atropine. The mean KB value (determined with acetylcholine as agonist) was 3.85 X 10(-11) M, and the corresponding pA2 value 10.43. At higher doses, the parasympathomimetics produced a contraction. This effect, too, was inhibited in a competitive manner with atropine. The calculated mean KB value with acetylcholine as agonist was 1.12 X 10(-11) M, and pA2 was 10.07. The motor responses did not require an intact perivascular sympathetic innervation, which shows that the effects were mediated by muscarinic type of cholinergic receptors present in the smooth musculature. In another series of experiments, pial arteries were preincubated in the presence of 3H-norepinephrine, and the amount of tritium efflux was measured in a superfusion system before or during electrical field stimulation (12 V, 1 msec pulse duration, 10 Hz). The efflux was minimized by sympathetic denervation, and the effect of transmural stimulation abolished by bretylium and guanethidine, which shows that the bulk of tritium overflow during stimulation originated from the perivascular sympathetic nerves. The marked elevation of tritium efflux during stimulation was enhanced by hexamethonium, and it was inhibited by nicotine and acetylcholine, whose effects were counteracted by hexamethonium (but not by atropine). This finding indicates the presence of nicotinic type of cholinergic receptors on the perivascular adrenergic nerves, allowing inhibition of norepinephrine by acetylcholine that may be liberated from the adjacent cholinergic terminals in the autonomic nerve plexus.

Acetylcholine↗
PubMed1977

Effects of autonomic drugs on the cardiovascular system: dogs with achalasia (under halothane anesthesia).

The parasympathetic and sympathetic components of the autonomic systems as they relate to cardiovascular function were studied on dogs with achalasia of the esophagus. This was accomplished by administering the parasympathomimetic drugs methacholine (0.2 mg/kg, subcutaneously), 2 doexy-D-glucose (100 mg/kg, intravenously (IV), the parasympatholytic drug atropine (0.2 mg/kg, IV), the sympathomimetic agent epinephrine (2.5 microng/kg, IV), and the beta adrenergic blocker propranolol (0.5 mg/kg, IV); and then measuring cardiac output, stroke volume, heart rate, mean arterial pressure, pulse pressure, central venous pressure, total peripheral resistance, PaCO2, PaO2, pH, and base deficit. Cardiovascular responses to the administration of the parasympathomimetic drugs, methacholine and 2 deoxy-D-glucose, or the parasympatholytic drug, atropine, were similar to those observed in normal dogs. Cardiovascular responses to the administration of the sympathomimetic drug epinephrine and the sympatholytic drug propranolol or beta blocker were also consistent with those observed in normal dogs. It can be interpreted from this pharmacologic evidence that parasympathetic and sympathetic innervations to the cardiovascular system are present in dogs with achalasia of the esophagus. Fewer cardiovascular variables were significantly altered in dogs with achalasia than in normal dogs. Since this was true for both the sympathetic and the parasympathetic values, it is interpreted as reflecting their general health rather than a specific lesion.

Anesthesia, Inhalation↗
PubMed1977

Analysis of drugs by pyrolysis. I. Selected ion monitoring combined with a pyrolysis method for the determination of carpronium chloride in biological samples.

In order to establish an analytical method for carpronium chloride, a parasympathomimetic agent, the pyrolysis reaction of carpronium chloride was examined in a g.c.m.s. system, which revealed that gamma-butyrolactone was produced directly from the drug as the main pyrolysis product. In the case of conversion of [2,2,3,3-2H4]carpronium chloride into the deuterated gamma-butyrolactone, 2H/1H scrambling was observed and confirmed to occur during the pyrolysis process of the deuterated compound. The proportion of gamma-[2H4]butyrolactone among the pyrolysis products was almost independent of the operating conditions, so [2,2,3,3-2H4]carpronium chloride was of practical use as an internal standard for selected ion monitoring. By incorporation of the pyrolysis reaction of carpronium chloride with selected ion monitoring and the use of [2,2,3,3-2H4]carpronium chloride as an internal standard, a rapid, sensitive and selective method was devised for the determination of the drug in biological samples. The method was utilized successfully for the biopharmaceutical studies of carpronium chloride in ma.

4-Butyrolactone↗
PubMed1980

Analysis of drugs by pyrolysis. II--An improved method for the determination of carpronium chloride in plasma by selected ion monitoring.

A sensitive and specific method has been devised for the determination of carpronium chloride, a parasympathomimetic agent, in plasma. The method is based on selected ion monitoring combined with the pyrolysis reaction of (3-isopropoxycarbopropyl)trimethylammonium chloride derived by transesterification of the drug. Carpronium chloride-[2H9] is used as an internal standard. The drug and the internal standard are separated from deproteinized plasma by ion pair extraction, and converted into isopropyl ester derivatives. The derivatives are pyrolysed to produce the respective isopropyl N,N-dimethyl-gamma-aminobutyrates available for selected ion monitoring. Measurement is carried out in the electron impact mode by monitoring the fragment ion [M-OC3H7]+ (m/z 114, 120). The method is applicable to 5 ng ml-1 plasma with about 10% coefficient of variation, and has been utilized successfully for the pharmacokinetics of carpronium chloride in man.

Animals↗
PubMed1986

Prostanoid synthesis by the rat urinary bladder: evidence for stimulation through muscarine receptor-linked calcium channels.

An in vitro model for the study of muscarine receptor-mediated synthesis of prostacyclin (PGI2) and other prostanoids (PGE2 and PGF2 alpha) by the rat urinary bladder is described. PGI2 synthesis was stimulated by parasympathomimetic agents (carbachol greater than methacholine greater than arecoline; McNA 343, nicotine and dimethyl phenyl piperazinium were without effect). Methacholine (3 X 10(-6) mol X l-1)-stimulated PGI2 synthesis was inhibited by muscarinic antagonists (atropine greater than ipratroprium bromide greater than gallamine greater than pirenzepine) and was completely abolished by the presence of ethylene diamine tetraacetic acid (EDTA: 10 mmol X l-1). Verapamil also inhibited methacholine-stimulated PGI2 synthesis in a dose-dependent manner. The antagonistic action of atropine was shown to be competitive, but had no effect on calcium ionophore A23187-stimulated PGI2 synthesis. High concentrations of [K+] (up to 0.11 mol X l-1) were without effect on PGI2 synthesis. PGE2, PGF2 alpha and PGI2 synthesis were all equally stimulated with methacholine, carbachol, arecoline and A23187, and methacholine-stimulated synthesis of these prostanoids was equally inhibited by atropine, ipratroprium bromide, gallamine, verapamil and EDTA. It is concluded that in vitro prostanoid synthesis by the rat urinary bladder: is stimulated by post ganglionic muscarine receptors; involves a muscarine receptor-linked calcium influx system; and is mediated by a predominance of M2 subtype receptors.

Animals↗
PubMed1997

Early resolution of Ogilvie's syndrome with intravenous neostigmine: a simple, effective treatment.

PURPOSE: Our aim was to assess the value of a parasympathomimetic drug (neostigmine) in the early resolution of acute colonic pseudo-obstruction (Ogilvie's syndrome). METHODS: A prospective study was undertaken in 18 consecutive patients (mean age, 76 (range, 31-87) years) with acute colonic pseudo-obstruction. After a varying period of conservative treatment in all cases, 16 patients with persistent, massive abdominal distention were given intravenous neostigmine. RESULTS: A rapid and satisfactory clinical and radiologic decompression of the large bowel was obtained in 12 patients (75 percent) after a single dose of the drug; another patient had complete resolution after a second dose, and the other 3 patients had only partial resolution, in one of them after a second dose of the drug. No patient required surgical decompression of the bowel. CONCLUSION: These results give support to the theory of excessive parasympathetic suppression in most cases of Ogilvie's syndrome. The treatment with intravenous neostigmine has proved very effective, preventing in many cases prolonged periods of uncomfortable and potentially hazardous conventional conservative management and avoiding surgical treatment in a consecutive series of patients.

Acute Disease↗
PubMed1997

Effects of antiglaucoma drugs on ocular hemodynamics in healthy volunteers.

BACKGROUND AND PURPOSE: There is evidence that ocular blood flow plays a critical role in the clinical course of glaucoma. Hence a reduction in ocular blood flow due to topical antiglaucoma treatment should be avoided. The purpose of this study was to characterize the effect of antiglaucoma drugs on ocular hemodynamics. METHODS: In a double-blind, placebo-controlled, randomized crossover study, we investigated the effects of single topical doses of five beta-blocking agents (befunolol, betaxolol, levobunolol, metipranolol, and timolol), two adrenergic agents (clonidine and dipivefrin [INN, dipivefrine]), and a parasympathomimetic agent (pilocarpine) on ocular and systemic hemodynamics in healthy subjects (n = 10). Fundus pulsation amplitudes in the macula and the optic disc were measured to characterize pulsatile choroidal and optic disc blood flow, respectively. Moreover, central retinal and ophthalmic artery blood flow velocities were measured by Doppler ultrasound. RESULTS: Befunolol, metipranolol, timolol, clonidine, and dipivefrin reduced fundus pulsations in the macula and the optic disc (-9% to -14% versus baseline). In contrast, betaxolol, levobunolol, and pilocarpine had no effect on fundus pulsations. Antiglaucoma drugs had no effect on either blood flow velocities in the central retinal or the ophthalmic artery or systemic hemodynamics. CONCLUSIONS: Our results indicate that befunolol, metipranolol, timolol, clonidine, and dipivefrin reduce choroidal and optic disc blood flow. This could be caused by drug diffusion to the choroid, which may cause vasoconstriction. Ocular blood flow reduction was not observed with betaxolol, levobunolol, or pilocarpine. The lack of effect of all drugs under study on central retinal blood flow velocity might partially be the result of autoregulative mechanisms. Because optic nerve head blood flow likely plays a critical role in the clinical course of glaucoma, the use of antiglaucoma drugs, which reduce blood flow, should be reconsidered.

Adrenergic Agents↗
PubMed2001

Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data.

This paper has reviewed the documentation on the clinical efficacy of choline alphoscerate, a cholinergic precursor, considered as a centrally acting parasympathomimetic drug in dementia disorders and in acute cerebrovascular disease. Thirteen published clinical trials, examining in total 4054 patients, have evaluated the use of choline alphoscerate in various forms of dementia disorders of degenerative, vascular or combined origin, such as senile dementia of the Alzheimer's type (SDAT) or vascular dementia (VaD) and in acute cerebrovascular diseases, such as transitory ischemic attack (TIA) and stroke. Analysis has assessed the design of each study, in particular with respect to experimental design, number of cases, duration of treatment and tests used to evaluate drug clinical efficacy. Most of the ten studies performed in dementia disorders were controlled trials versus a reference drug or placebo. Overall, 1570 patients were assessed in these studies, 854 of which in controlled trials. As detected by validated and appropriate tests, such as Mini Mental State Evaluation (MMSE) in SDAT and Sandoz Clinical Assessment Geriatric (SCAG) in VaD, administration of choline alphoscerate significantly improved patient clinical condition. Clinical results obtained with choline alphoscerate were superior or equivalent to those observed in control groups under active treatment and superior to the results observed in placebo groups. Analysis stresses the clear internal consistency of clinical data gathered by different experimental situations on the drug effect, especially with regard to the cognitive symptoms (memory, attention) characterising the clinical picture of adult-onset dementia disorders. The therapeutic usefulness of choline alphoscerate in relieving cognitive symptoms of chronic cerebral deterioration differentiates this drug from cholinergic precursors used in the past, such as choline and lecithin. Three uncontrolled trials were performed with choline alphoscerate in acute cerebrovascular stroke and TIA, totalling 2484 patients. The results of these trials suggest that this drug might favour functional recovery of patients with cerebral stroke and should be confirmed in future investigations aimed at establish the efficacy of the drug in achieving functional recovery of patients with acute cerebrovascular disease.

Cerebrovascular Disorders↗
PubMed1996

The diseases of Alzheimer and Pick from the viewpoint of prevention.

Alzheimer disease, Pick disease and senile dementia are all characterized by similar morphological changes, both macroscopic and microscopic, and similar psychiatric symptoms. All three should, therefore, be viewed as aspects of one disease, which is termed Alzheimer-type dementia. Nothing contradicts the view that immune complexes take part in the etiology of Alzheimer-type dementia. There are various types of immune complexes and so their points of action in the organism may vary. There might be two main means of preventing Alzheimer-type dementia: the first could be named the serological (basic) and the second relying on pharmacotherapy (additional). Pharmacological prevention of disease might be aided by the use of parasympathomimetic drugs, e.g. pilocarpine.

Aged↗
PubMed1984

Review of ciliary muscle effort in presbyopia.

Fincham's theory of presbyopia would require maximum ciliary muscle contraction to produce maximum accommodative response at all ages. The Hess-Gullstrand theory, however, would allow a maximum accommodative response with a decreasing ciliary muscle contraction as age increases leaving a reserve ability of ciliary muscle to contract with age. If Fincham's theory is correct, a mild parasympatholytic drug would produce a decrease in the amplitude of accommodation, a mild parasympathomimetic drug would produce an increase in the amplitude of accommodation, and the AC/A ratio would increase with age. The results of this study indicate that all three of these do occur and therefore support the Fincham concept of the cause of presbyopia.

Accommodation, Ocular↗
PubMedDate not supplied

Neurotoxic mycotoxins: a review of fungal toxins that cause neurological disease in large animals.

Five mycotoxins found in concentrates or roughages have been shown to cause neurologic disease in livestock. Fumonisin B1 is produced by Fusarium moniliforme and causes leukoencephalomalacia in horses. Swainsonine and slaframine are produced by Rhizoctonia leguminicola and cause mannose accumulation and parasympathomimetic effects, respectively. Lolitrems from Acremonium lolii and paspalitrems from Claviceps paspali are tremorgens found in grasses.

Alkaloids↗
PubMed1984

Autonomic regulation of mucociliary transport rate in the oesophagus of the frog, Rana temporaria.

Transport of lead particles along the mucosal surface of the frog oesophagus has been measured by direct observation with the aid of video recording. Electrical stimulation of the vagus nerve increased the rate of particle transport. This acceleration was suppressed by atropine or by hexamethonium. Acetylcholine and other parasympathomimetic agents accelerated particle transport rate. Such acceleration was abolished by atropine. Nicotine increased the rate of particle transport and this effect was suppressed by hexamethonium or by atropine. Atropine did not significantly alter basal particle transport rate. Neither basal particle transport rate nor the response to vagal nerve stimulation were affected by eserine. Adrenaline, noradrenaline or isoprenaline did not affect basal particle transport rate. Adrenaline or noradrenaline were without effect on the increased particle transport rate due to electrical stimulation of the vagus.

Animals↗
PubMed1990

Electrical properties of smooth muscle cell membrane in renal pelvis of rabbits.

Intracellular recordings were made to study the electrical properties of smooth muscle cells in the rabbit renal pelvis. The muscle cells exhibited spontaneous oscillation in the membrane potential (slow wave). The slow waves were regular and were resistant to tetrodotoxin and sympathomimetic or parasympathomimetic antagonists, findings indicative of myogenic activity. The membrane was depolarized by an increase in extracellular concentration of K+ ([K+]o), decrease in [Na+]o, inhibition of the electrogenic Na(+)-K+ pump by ouabain or K(+)-free solution, and the application of norepinephrine (NE, greater than 10(-6) M). The maximum slope of the membrane depolarization produced by a 10-fold increase in [K+]o was approximately 48 mV. Reductions in [Ca2+]o inhibited the generation of slow waves with no marked change in the membrane potential. Depolarizations produced by any given method increased the frequency and decreased the amplitude of the slow wave, and NE had the most potent accelerating action on the frequency. Hyperpolarization of the membrane by 1-5 mV with extracellularly applied current stimuli reduced the frequency, and a strong hyperpolarization (greater than 5 mV) blocked the generation of slow waves. Electrophysiological properties of the slow waves obtained with tissues of the renal pelvis and intestinal smooth muscles were compared.

Animals↗
PubMed1987

Effect of resting smooth muscle length on contractile response in resistance airways.

We studied the effect of resting smooth muscle length on the contractile response of the major resistance airways (generations 0-5) in 18 mongrel dogs in vivo using tantalum bronchography. Dose-response curves to 10(-10) to 10(-7) mol/kg methacholine (MCh) were generated [at functional residual capacity (FRC)] by repeated intravenous bolus administration using tantalum bronchography after each dose. Airway constriction varied substantially with dose-equivalent stimulation and varied sequentially from trachea (8.8 +/- 2.2% change in airway diam) to fifth-generation bronchus (49.8 +/- 3.0%; P less than 0.001). Length-tension curves were generated for each airway to determine the airway diameter (i.e., resting in situ smooth muscle length) at which maximal constriction was elicited using bolus intravenous injection of 10(-8) mol/kg MCh. A Frank-Starling relationship was obtained for each airway; the transpulmonary pressure at which maximal constriction was elicited increased progressively from 2.50 +/- 1.12 cmH2O for trachea (approximately FRC) to 18.3 +/- 1.05 cmH2O for fifth-generation airways (approximately 50% TLC) (P less than 0.001). A similar relationship was obtained when change in airway diameter was plotted as a function of airway radius. We demonstrate substantial heterogeneity in the lung volumes at which maximal constriction is elicited and in distribution of parasympathomimetic constriction within the first few generations of resistance bronchi. Our data also suggest that lung hyperinflation may lead to augmented airway contractile responses by shifting resting smooth muscle length toward optimum resting smooth muscle length.

Airway Resistance↗
PubMed1993

Tropical pasture hay utilization with slaframine and cottonseed meal: ruminal characteristics and digesta passage in wethers.

Sixteen mature, ruminally cannulated wethers (average BW = 41 +/- 1 kg) were fed a low-quality hay diet with or without a cottonseed meal (CSM) supplement and the parasympathomimetic agonist slaframine (SF). Treatments were basal diet (Mitchell grass hay, 4.8% CP, 46.8% ADF) available on an ad libitum basis, basal diet plus SF (8 micrograms/kg BW, 2 x daily i.m. injection), basal diet plus CSM (41.0% CP; 100 g/d), or basal diet plus SF and CSM. Treatments were arranged as a 2 x 2 factorial within a replicated 4 x 4 Latin square with 20-d periods followed by a 10-d adjustment during which only the basal diet was fed. All measurements were performed within the final 10 d of each period. Slaframine increased salivary flow by 10 to 35% (P < .07), ruminal fluid dilution rate by 8 to 11% (P < .10), and pH by 3 to 4% (P < .001). A twofold increase (P < .05) in ruminal cellulolytic bacteria numbers occurred in SF-treated wethers. Despite these SF-induced changes in the ruminal environment, whole-tract apparent nutrient digestibility, N and mineral balance, and ruminal VFA concentrations were not changed. Cottonseed meal increased forage intake by 34 to 54% (P < .001) and DM digestibility by 30% (P < .001). Cottonseed meal supplementation of a Mitchell grass hay diet improved nutritional status and attenuated live weight loss.

Alkaloids↗