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PubMed1998

Conformationally constrained analogues of the muscarinic agonist 3-(4-(methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyr idine. Synthesis, receptor affinity, and antinociceptive activity.

Conformationally constrained analogues of the potent muscarinic agonist 3-(4-methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methy lpyridine (methylthio-TZTP, 17) were designed and synthesized with the aim of (a) improving the antinociceptive selectivity over salivation and tremor and (b) predicting the active conformation of 17 with respect to the dihedral angle C4-C3-C3'-N2'. Using MOPAC 6.0 tricyclic analogues (7, 15, 16) with C4-C3-C3'-N2' dihedral angles close to 180 degrees and a rotation hindered analogue (9) with a C4-C3-C3'-N2' dihedral angle close to 274 degrees were designed, as these conformations had previously been suggested as being the active conformations. The analogues were tested for central muscarinic receptor binding affinity, for their antinociceptive activity in the mouse grid shock test, and, in the same assay, for their ability to induce tremor and salivation. The data showed that the tricyclic analogues (7, 15, 16) were equipotent with 17 as analgesics, but with no improved side effect profiles. The rotation-hindered analogue 9 had neither muscarinic receptor binding affinity nor antinociceptive activity. These results suggest that the active conformation of 17 has a C3-C4-C3'-N2' dihedral angle close to 180 degrees.

Analgesics↗
PubMed2000

Efficacy and safety of premedication with oral ketamine for day-case adenoidectomy compared with rectal diazepam/diclofenac and EMLA.

BACKGROUND: Because of its pain-attenuating and sedative properties oral ketamine has been used as premedication in children and adults. We wanted to compare in children scheduled for adenoidectomy safety and efficacy of oral ketamine with a premedication that causes similar preoperative sedation and relief of pain at the venepuncture site. We also evaluated the effect of i.v. glycopyrrolate added to these combinations. METHODS: One hundred children between 10 and 15 kg of body weight scheduled for day-case adenoidectomy were randomly assigned to one of four groups: groups DG and DS received diclofenac 12.5 mg and diazepam 0.5 mg/kg rectally, EMLA cream at the venepuncture site, and placebo orally; groups KG and KS received ketamine 6.0 mg/kg orally, placebo cream at the puncture site, and placebo rectally; additionally, groups DG and KG received glycopyrrolate 5 microg/kg, and groups DS and KS received placebo intravenously. We recorded perioperatively scores (open scale 1-9) for stridor, sedation, bleeding, nausea, pain, heart rate, the need for analgesics and registered psychotomimesis and well-being at home. RESULTS: The children of the K-groups became more tearful during separation from their parents (P=0.0072). No other differences were found between the ketamine and diazepam/diclofenac groups before and after premedication until induction of anaesthesia. Oral ketamine produced unpleasant psychotomimesis in four out of 59 children. During the first 10 min postoperatively, the score for stridor was significantly higher in group KS than in the D-groups; stridor scores > or = 6 were seen in one child of the D-groups (DS) and in six children of the K-groups (n.s.), of whom three developed laryngospasm (one reintubation). Glycopyrrolate diminished salivation in all groups, but had no effect on stridor scores. Additionally, glycopyrrolate delayed the onset of eating at home. CONCLUSION: Premedication with racemic oral ketamine 6 mg/kg does not seem to be suitable for upper airway procedures. Addition of i.v. glycopyrrolate before the induction of anaesthesia significantly reduced the scores for salivation.

Adenoidectomy↗
PubMed2005

2-Furoyl-LIGRL-NH2, a potent agonist for proteinase-activated receptor-2, as a gastric mucosal cytoprotective agent in mice.

1. Proteinase-activated receptor-2 (PAR(2)), expressed in capsaicin-sensitive sensory neurons, plays a protective role in gastric mucosa. The present study evaluated gastric mucosal cytoprotective effect of 2-furoyl-LIGRL-NH(2), a novel highly potent PAR(2) agonist, in ddY mice and in wild-type and PAR(2)-knockout mice of C57BL/6 background. 2. Gastric mucosal injury was created by oral administration of HCl/ethanol solution in the mice. The native PAR(2)-activating peptide SLIGRL-NH(2), administered intraperitoneally (i.p.) at 0.3-1 micromol kg(-1) in combination with amastatin, an aminopeptidase inhibitor, but not alone, revealed gastric mucosal protection in ddY mice, which was abolished by ablation of capsaicin-sensitive sensory neurons. 3. I.p. administration of 2-furoyl-LIGRL-NH(2) at 0.1 micromol kg(-1), without combined treatment with amastatin, exhibited gastric mucosal cytoprotective activity in ddY mice, the potency being much greater than SLIGRL-NH(2) in combination with amastatin. This effect was also inhibited by capsaicin pretreatment. 4. Oral administration of 2-furoyl-LIGRL-NH(2) at 0.003-0.03 micromol kg(-1) also protected against gastric mucosal lesion in a capsaicin-reversible manner in ddY mice. 5. I.p. 2-furoyl-LIGRL-NH(2) at 0.1-0.3 micromol kg(-1) caused prompt salivation in anesthetized mice, whereas its oral administration at 0.003-1 micromol kg(-1) was incapable of eliciting salivation. 6. In wild-type, but not PAR(2)-knockout, mice of C57BL/6 background, i.p. administration of 2-furoyl-LIGRL-NH(2) caused gastric mucosal protection. 7. Thus, 2-furoyl-LIGRL-NH(2) is considered a potent and orally available gastric mucosal protective agent. Our data also substantiate a role for PAR(2) in gastric mucosal protection and the selective nature of 2-furoyl-LIGRL-NH(2).

Animals↗
PubMed2003

Effects of mixed-action kappa/mu opioids on cocaine self-administration and cocaine discrimination by rhesus monkeys.

kappa-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed kappa/mu receptor activity is unclear. The effects of three mixed kappa/mu agonists (MCL-101, (-)cyclorphan, and Mr2034) and one kappa-selective agonist (enadoline) on cocaine self-administration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all kappa agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose-effect curve (0.001-0.32 mg/kg/inj, i.v.). During 7 days of chronic treatment, (-)cyclorphan (0.0032-0.032 mg/kg/h) and MCL-101 (0.0032-0.032 mg/kg/h) each dose dependently reduced cocaine self-administration maintained by a dose near the peak of the cocaine self-administration dose-effect curve. MCL-101 (0.032 mg/kg/h) produced selective and sustained decreases in cocaine self-administration, whereas (-)cyclorphan (0.032 mg/kg/h) had selective but transient effects. In addition, these mixed kappa/mu agonists produced fewer side effects (some salivation) than the kappa-selective agonist (sedation, salivation, emesis). However, none of these kappa agonists substituted for or antagonized cocaine's discriminative stimulus effects in monkeys trained to discriminate cocaine (0.4 mg/kg, i.m.) from saline. Thus, kappa and mixed kappa/mu-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed kappa/mu agonists appear to offer some advantages over selective kappa agonists as potential treatments for cocaine abuse.

Analgesics, Non-Narcotic↗
PubMed1996

Comparison of the effects of clonidine on tyramine- and methoxamine-evoked mydriasis in man.

1. It has been reported previously that clonidine can potentiate tyramine-evoked mydriasis on the pain-free side of cluster headache patients. We examined whether a single oral dose of clonidine (200 micrograms) can also potentiate tyramine-evoked mydriasis in healthy subjects, using mydriasis to methoxamine, a directly acting sympathomimetic amine, as a control. 2. Eight healthy male volunteers participated in four weekly sessions. In the first two sessions (Experiment 1) the effect of clonidine or placebo on the mydriasis to tyramine hydrochloride eyedrops (75 mM; 2 x 10 microliters), and in the last two sessions (Experiment 2) the effect of clonidine or placebo on the mydriasis to methoxamine hydrochloride eyedrops (20 mM; 2 x 10 microliters) was examined. In both experiments subjects were allocated to drugs and sessions according to a double-blind balanced design. In both experiments, pupil diameter of both the treated and the untreated eyes was recorded in standard ambient light and in the dark, before, and 2 h after clonidine/placebo, via binocular infrared television pupillometry. Salivation (dental roll technique), systolic and diastolic blood pressure (sitting), heart rate, and self-ratings of mood and feelings (visual analogue scales), were also measured before, and 2 h after the ingestion of clonidine or placebo. 3. Both tyramine and methoxamine produced a significant mydriasis, which was more prominent in the light condition (change in resting pupil size; mm +/- s.e.mean: tyramine/light 1.05 +/- 0.28; tyramine/dark: 0.73 +/- 0.15; methoxamine/light: 1.65 +/- 0.28; methoxamine/dark: 0.85 +/- 0.15). Clonidine produced a significant miosis in the untreated eye which was more prominent in the light condition (change in resting pupil size; mm +/- s.e.mean: Experiment 1, light: -1.34 +/- 0.19; Experiment 1, dark: -0.46 +/- 0.1; Experiment 2, light -0.97 +/- 0.18; Experiment 2, dark: -0.29 +/- 0.17). Clonidine had no significant effect on either tyramine- or methoxamine-evoked mydriasis. 4. In agreement with previous reports, clonidine significantly reduced salivation (g, mean +/- s.e.mean; Experiment 1: -0.84 +/- 0.22; Experiment 2: -0.55 +/- 0.11), systolic blood pressure (mm Hg; Experiment 1: -17.5 +/- 3.76; Experiment 2: -23.38 +/- 4.67), diastolic blood pressure (mm Hg; Experiment 2: -12.38 +/- 2.05), alertness (mm; Experiment 2: -24.19 +/- 5.40), and anxiety (mm; Experiment 1: -13.82 +/- 4.60), indicating the presence of pharmacodynamically effective tissue levels of the drug. 5. These results show that a single oral dose (200 micrograms) of clonidine causes significant miosis in human subjects, and fails to potentiate tyramine-evoked mydriasis. This indicates that the pupil on the asymptomatic side of cluster headache patients is affected differently from the pupils of healthy volunteers by tyramine and/or clonidine.

Adolescent↗
PubMed1979

The abundance of pathogenic African trypanosomes in the salivary secretions of wild Glossina pallidipes.

Trypanosome infection rates in wild Glossina pallidipes from the Lambwe Valley, Kenya, were determined using salivation and fly dissection methods. Of the 416 flies examined by salivation, one was infected with Trypanosoma brucei, seven with T. congolense, 18 with T. vivax and three with both T. congolense and T. vivax. The fly infected with T. brucei always secreted saliva heavily infected with trypanosomes. Flies infected with T. vivax secreted saliva which contained very few trypanosomes and some of these flies produced negative saliva for several successive days. There was no significant difference between the proportions of male and female flies which were infected with any one species of trypanosome, but there were highly significant differences between the mean numbers of the different species of trypanosome in the saliva.

Animals↗
PubMed1994

Imagery and craving in alcohol dependent persons.

There is limited evidence supporting the effectiveness of imagery techniques in exposure-based treatments for alcohol dependence. Changes in craving for alcohol following imagery instruction, measured by cognitive and physiological indices, have not been demonstrated. Furthermore, the influence of different imagery script content has not been investigated. This study compared levels of craving elicited, measured by self-report and salivation, under control and imagery conditions, in subjects receiving treatment for alcohol dependence. Imagery script content was varied across three levels. Participants generally reported forming good quality images with strong affective components. Significant effects of imagery treatment were found for changes in self-reported craving levels, but not for the salivation measure. Significant decay in levels of self-reported craving was also observed. No differences in effectiveness between the three script types were discovered. Implications of the results for therapy approaches such as cue exposure are considered.

Journal Article↗
PubMed1998

Phospholipase A2 activity in salivary glands and saliva of the lone star tick (Acari: Ixodidae) during tick feeding.

Phospholipase A2 (PLA2) activity levels in tick [Amblyomma americanum (L.)] salivary glands and saliva were examined during tick feeding by using 14C-phosphatidylcholine as the substrate. Saliva produced by stimulating female ticks to salivate with dopamine contains PLA2 (ts-PLA2) activity. The ts-PLA2 activity level in saliva did not change significantly during tick feeding except for a decrease in the last rapid feeding phase (> 200 mg) and in replete ticks. Phospholipase A2 activity was higher in salivary glands of fed than unfed ticks, both in males and females; activity increased during tick feeding correlating with salivary secretory rates during tick feeding suggesting that much of the PLA2 activity measured in whole salivary glands is synthesized for subsequent secretion. During the time course of in vitro salivation, the first 10 microliters of saliva contained higher ts-PLA2 activity than saliva secreted thereafter. Phospolipase A2 was identified in the saliva of artificially fed ticks indicating that ts-PLA2 is a physiological component of tick saliva.

Animals↗
PubMed1985

The symptoms of patients treated for Parkinson's disease.

One hundred and eighty-one patients with treated Parkinson's disease completed a self-administered questionnaire on symptoms, and their responses were compared with those of 263 control subjects randomly selected from a general practice population. Nine symptoms were reported by the patients with more than a fivefold excess when compared with the controls. These included jerking of the limbs, shaking of the hands, excessive salivation, poor mental concentration, grimacing, being frozen or rooted to the spot, and hallucinations. Compared with the general control population, the patients did not have an excess of stomach or limb pain, indigestion, headache, or any decrease of interest in sex. This observational survey, unlike a randomised controlled trial, could not ensure that the different treatment groups were comparable in important respects. However, certain associations were apparent; for example, patients receiving both a decarboxylase inhibitor and levodopa tended to report fewer attacks of being frozen to the spot, fewer problems with salivation, and a reduced frequency of defaecation. Patients receiving anticholinergic drugs reported an excess of dry mouth, faintness, and dyskinesia, and fewer hot flushes.

Adult↗
PubMed1999

Carbamate and organophosphate poisoning in young children.

OBJECTIVE: Retrospective evaluation of the clinical course of carbamate and organophosphate poisoning in young children. DESIGN: The records of 36 children intoxicated with carbamate and 16 children intoxicated with organophosphate (age range: 2 to 8 years, median: 2.8 years) were examined retrospectively. The carbamate agents were identified as methomyl or aldicarb, and the organophosphate as parathion, fenthion, malathion, and diazinon. The causes of poisoning were accidental ingestion in 46 children and inhalation in six children. CLINICAL SETTING: Pediatric Intensive Care Unit of a teaching hospital. INTERVENTIONS: Gastric lavage was performed, and activated charcoal was administered to all children who had ingested poisonous pesticides. Atropine sulphate was administered intravenously in repeated doses to all children with bradycardia, diarrhea, salivation, and miosis. Obidoxime chloride was administered to patients with organophosphate poisoning and to those in whom the ingested material was unidentified on admission. RESULTS: Predominant symptoms were related to central nervous system depression and severe hypotonia. Other clinical signs such as miosis, diarrhea, salivation, bradycardia, and fasciculation were less frequent, while tearing and diaphoresis were not observed. Pulmonary edema developed in six patients with organophosphte poisoning. Three children required mechanical ventilation for several hours. One child (organophosphate poisoning) died shortly after arrival at the emergency department. All other children recovered completely. CONCLUSION: Based on a relatively large group of young pediatric patients with carbamate and organophosphate poisoning, it is concluded that the clinical presentation differed from those described in adults. Absence of classic muscarinic effects does not exclude the possibility of cholinesterase inhibitor agents poisoning in young children with central nervous system depression.

Adult↗
PubMed2000

Smoking and gastro-oesophageal reflux disease.

The role of smoking in the pathogenesis of gastrooesophageal reflux disease has been controversial since the early 1970s when Stanciu reported the two to be 92% epidemiologically associated (a study subsequently challenged by inconsistencies in the observational data). Mechanistically, reflux disease is caused by excessive oesophageal acid exposure, which is potentially attributable to excessive reflux events and/or prolonged acid clearance. Currently, the best available pH monitoring data confirm that smoking increases oesophageal acid exposure. Smoking reduces lower oesophageal sphincter (LOS) pressure and predisposes to strain-induced reflux. Consistent with this, smoking has been shown to cause an increased number of reflux events that are not attributable to increased transient LOS relaxations, but rather are associated with deep inspiration and coughing. Once reflux occurs, acid is cleared from the oesophagus by a two-step process consisting of oesophageal peristalsis followed by neutralization of the residual acid by swallowed saliva. Smoking prolongs acid clearance by decreasing salivation. The effects of smoking on LOS tone and acid clearance are most likely mainly due to nicotine but are incompletely understood. Transdermal nicotine has similar effects to smoking on LOS pressure and salivation. Thus, although perhaps not a dominant risk factor, smoking and nicotine impact on pathophysiological variables of gastro-oesophageal reflux disease. In itself, smoking cessation is unlikely to cure severe gastrooesophageal reflux disease, but, along with appropriate pharmacological therapy, it may be beneficial.

Controlled Clinical Trials as Topic↗
PubMed1990

Sorbitol-fermenting predominant cultivable flora of human dental plaque in relation to sorbitol adaptation and salivary secretion rate.

The sorbitol-fermenting predominant flora of human dental plaque was studied in 12 people with low and 11 with normal salivary secretion rates before and after a period of frequent mouth rinses with sorbitol solution. A total of 277 sorbitol-fermenting isolates are described by their morphological and physiological characteristics. The flora was almost exclusively composed of gram-positive bacteria belonging to the genera Streptococcus, Lactobacillus and Actinomyces in people with low secretion rates and Streptococcus and Actinomyces in those with normal salivation. At the species level, Streptococcus mutans predominated in all. The frequent use of sorbitol resulted in an increase of the streptococcal species mainly and particularly of Streptococcus sanguis I in people with normal salivation. The counts of lactobacilli and Actinomyces remained unaffected. Almost all isolates appeared to belong to the resident plaque flora. Succession of new sorbitol-fermenting genera to the plaque community could not be observed as a result of the frequent exposure of the mouth to sorbitol.

Adaptation, Biological↗
PubMed2004

Anti-nociceptive and sedative effects of sufentanil long acting during and after sevoflurane anaesthesia in dogs.

The purpose of the present study was to determine the most effective time interval between the administration of sufentanil long acting (LA) and the induction of sevoflurane anaesthesia in dogs. The occurrence of sedation, analgesia and other marked side-effects were evaluated in addition to the possible dosage-reducing effect of sufentanil on sevoflurane in dogs. Forty clinically normal beagles aged 1-2 years and weighing between 8.4 and 13.6 kg were included. Two control groups were used: one group of dogs (A) received sufentanil LA (50 microg/kg i.m.) and a second group (B) the sufentanil vehicle followed by standard inhalation anaesthesia of 90 min. After premedication with sufentanil LA immediately before (C0), 15 min (D15) or 30 min (E30) prior to induction with thiopental (i.v.) the dogs were anaesthetized for 90 min with sevoflurane in oxygen. Pain and sedation scores were evaluated every 10 min during sevoflurane anaesthesia and at 2 (T120), 4 (T240) and 24 h (T1440) after initiation of anaesthesia. The occurrence of adverse reactions such as hypothermia, lateral recumbency, ataxia, noise sensitivity, vomiting, defaecation, salivation, nystagmus and excitation was observed at the same time-points. During the recovery period pain scores were lower and sedation scores higher in the sufentanil LA groups. In many dogs acceptable pain and sedation scores persisted during 24 h. Several dogs showed ataxia, lateral recumbency, arousal on auditory stimulation, defaecation, salivation and excitation at several time-points after sufentanil LA administration. Sufentanil LA in addition to sevoflurane anaesthesia offered beneficial dosage-reducing analgesic effects up to 69.8% for thiopental and 78.3% for sevoflurane; although several typical opioid side-effects occurred. To achieve this advantageous dosage-reducing effect 15 min should be respected between sufentanil LA administration and induction of sevoflurane anaesthesia.

Adjuvants, Anesthesia↗
PubMed1996

Clinical features of experimentally induced rabies in cattle and sheep.

A total of 20 cattle and five sheep out of a larger group of animals that were experimentally challenged with virus as part of the required protocol for a vaccine trial developed clinical signs of rabies. All five sheep and 18 of the cattle tested positive for rabies in a direct fluorescent antibody (FA) test. The remaining two cattle had suspicious FA results. Prospective observations are reported in this study. In the diseased cattle, the average incubation period was 15.1 days and the average morbidity period was 3.7 days. Of those, the naive cattle had significantly shorter incubation and morbidity periods than the test-vaccinated cattle. Major clinical signs included excessive salivation (100%), behavioural change (100%), muzzle tremors (80%), vocalization (bellowing; 70%), aggression, hyperaesthesia and/or hyperexcitability (70%), and pharyngeal paresis/paralysis (60%). The furious form of rabies was seen in 70% of the cattle. In the diseased sheep, the average incubation period was 10.0 days and the average morbidity period was 3.25 days. Major clinical signs included muzzle and/or head tremors (80%), aggressiveness, hyperexcitability, and/or hyperaesthesia (80%), trismus (60%), salivation (60%), vocalization (60%) and recumbency (40%). The furious form of rabies manifested in 80% of the sheep. Current rabies vaccines on the market contain higher effective doses than that utilized for the test vaccine and the results of this study do not reflect in any way on commercially available ruminant rabies vaccines.

Animals↗
PubMed1987

Is atropine a pilocarpine antagonist in cases of eliminated parasympathetic innervation of the human parotid salivary gland?

1 Following denervation of the human parotid salivary gland, pilocarpine caused an intensified stimulant response on salivation and a stimulant effect of atropine on salivary secretion was revealed. However, despite its stimulant effect on salivary secretion, atropine retained its action in blocking the salivatory response to pilocarpine. 2 This dualism in the action of atropine is explained by an action on different muscarinic receptor sub-types, i.e. on some sub-types atropine behaves as an antagonist and on others as an agonist. 3 Under the particular conditions in which the studies were performed, pilocarpine neither prevented nor increased the subsequent paradoxical response to atropine. Moreover, when injected at the peak of the atropine salivatory response it caused neither addition nor synergism to the atropine response. 4 Following the simultaneous injection of both pilocarpine and atropine, atropine initially suppressed the effect of pilocarpine and then itself caused a powerful paradoxical salivation. 5 Pilocarpine injected at the end of the paradoxical secretory response to atropine caused no secretion indicating that atropine retained its antisecretory effect against pilocarpine. 6 The extent of pilocarpine secretory responses is dependent upon the presence or absence of atropine, whilst the atropine effect is independent of the presence of pilocarpine. This points to the presence of differing populations of cholinoreceptors to explain the agonist effects of pilocarpine and atropine.

Atropine↗
PubMed1962

Effects of organophosphorous compounds, oximes and atropine injected into the third ventricle of unanaesthetized dogs.

The effects of four organophosphorous compounds, three oximes and atropine sulphate, injected through an indwelling cannula into the third ventricle of unanaesthetized dogs were examined. The effects of 200 mug of dyflos were involuntary micturition, defaecation, akinesia of hind limbs and pronounced disturbances of awareness; those of 100 mug of ethyl pyrophosphate were tremor, restlessness and signs of fear; 500 mug to 5 mg of dyflos and 250 mug to 500 mug of ethyl pyrophosphate caused vomiting, salivation, twitches of facial muscles and recurrent epileptiform seizures. The injection of 40 to 80 mg of dimefox and of 50 mg of schradan elicited involuntary micturition, vomiting, salivation and defaecation. These effects occur probably after these substances have passed into the blood stream and have been converted in the liver to potent anticholinesterases. This view is supported by the finding of reduced blood cholinesterase activity. At a dose level of 12.5 mg, 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) produced strong convulsions. At this dose level pralidoxime iodide and diacetyl monoxime produced no observable effects. Atropine sulphate in a dose of 1 mg caused disturbances in consciousness and behaviour followed by convulsions. Intraventricular atropine and to a minor extent intraventricular oximes were able to antagonize the effects of intraventricular ethyl pyrophosphate. Pralidoxime iodide exerted a strong antagonistic effect also on intravenous injection.

Animals↗
PubMed1992

GEA 857, a putative blocker of potassium conductance, enhances muscarinic agonist-evoked responses: dissociation from an action on 5-HT mechanisms.

GEA 857 [2-(4-chlorophenyl)-1,1-dimethylethyl 2-amino-3-methylbutanoate], a structural analogue of the 5-HT uptake blocker alaproclate, was tested for its ability to modify tremor and salivation induced by muscarinic agonists (oxotremorine, arecoline) and acetylcholinesterase inhibitors (physostigmine, THA) in the male rat. These agents were employed at submaximal doses. GEA 857, similarly to alaproclate (Ogren et al. 1985a & b), produced a dose-dependent, statistically significant (in the 5-20 mg/kg dose range) enhancement of the tremor response induced by all four cholinergic stimulants. However, unlike alaproclate, GEA 857 failed to enhance salivation in a consistent manner. GEA 857 itself did not produce tremor in the absence of the muscarinic agonists or the acetylcholinesterase inhibitors. The potentiation of oxotremorine tremor by GEA 857 could be fully blocked by atropine (1 mg/kg intraperitoneally). Unlike alaproclate, GEA 857 failed to affect 5-HT uptake or 5-HT metabolism in the 10-20 mg/kg dose range. However, similarly to the action of alaproclate, the potentiating effect of GEA 857 on muscarinic responses could be explained neither by actions on serotonergic mechanisms nor by actions on muscarinic receptor mechanisms in the striatum. Evidence is presented suggesting that the ability of GEA 857 to enhance responses evoked by muscarinic agonists involves inhibitory properties of GEA 857 at certain membranal Ca(2+)-dependent K+ channels, the blockade of which can potentiate or prolong muscarinic cholinergic actions.

Alanine↗
PubMed1990

Exocrine and endocrine release of kallikrein after reflex-induced salivary secretion.

Exocrine and endocrine release of rat submandibular gland kallikrein has been shown to be low after parasympathetic and beta-adrenergic stimulation but greatly increased after alpha-adrenergic stimulation. In the present study, release of glandular kallikrein was investigated under conditions known to give a reflex-induced salivary gland response. Heat stress induced a rich flow of saliva originating in the submandibular glands. Salivary kallikrein secretory rate was higher than after parasympathetic stimulation but lower than after sympathetic stimulation (P less than 0.005). Only heat stress increased circulating glandular kallikrein (12.7 +/- 0.8 ng ml-1 before heat exposure and 53.3 +/- 14.1 ng ml-1 40 min afterwards, P less than 0.005). There were no indications that the endocrine release of kallikrein was due to non-specific leakage. Atropine abolished heat-induced salivation and endocrine kallikrein secretion, possibly through interference with central pathways (P less than 0.05). However, phentolamine did not, which may indicate as an yet unidentified mediator of endogenous kallikrein release. The salivary gland response to acid and ether was comparable to that observed after parasympathetic nerve stimulation and was abolished by atropine (P less than 0.005). Stimuli known to influence other salivary gland ductal cells, such as aggression and starvation followed by drinking, also did not increase the plasma concentration of glandular kallikrein. The fact that various conditions which induce salivation did not increase circulating glandular kallikrein, coupled with the fact that kallikrein concentration was the highest in animals that died from heat stress, may suggest that the increase in circulating glandular kallikrein seen after heat stress may be pathological and could contribute to the development of heat shock.

Animals↗