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PubMed1990

Cardiovascular effects of flesinoxan in anaesthetized and conscious dogs.

Stimulation of 5-HT1A receptors is known to decrease the arterial blood pressure in anaesthetized rats, cats and dogs. We investigated the hypotensive activity of flesinoxan (0.1 + 0.2 + 0.7 mumol/kg), a 5-HT1A-receptor agonist, in dogs anaesthetized with either morphine and pentobarbital or enflurane and also in the conscious state. Flesinoxan led to a decrease in arterial blood pressure in anaesthetized, but not in conscious dogs. In the conscious state the marked increase in heart rate, which can be taken as an indicator of sympathetic tone, may have masked the consequences of vasodilatation. These different haemodynamic responses to flesinoxan may be dependent on side effects of the drug in the conscious dogs, in particular hyperventilation and salivation combined with anxiety, and on the magnitude of the decrease in baroreceptor reflex activity during anaesthesia with morphine and pentobarbital on the one hand and enflurane on the other hand.

Anesthesia↗
PubMed1992

Attenuation of the morphine withdrawal syndrome by inhibition of catabolism of endogenous enkephalins in the periaqueductal gray matter.

We have investigated the effects of the local administration into the periaqueductal gray matter of thiorphan, a selective inhibitor of endopeptidase 24.11 "enkephalinase", kelatorphan, (R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)- L-alanine, and RB 38 A, (R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)-L-phenylalanine, two almost complete inhibitors of enkephalin metabolism, on the naloxone-precipitated morphine withdrawal syndrome in rats. Local administration of these inhibitors decreased the severity of the withdrawal syndrome. Jumping, chewing, diarrhea, piloerection, salivation and hypothermia were decreased by all drugs. Lacrimation and weight loss were reduced by kelatorphan and RB 38 A whereas teeth chattering, tremor, eye twitch and rhinorrhea were decreased only by RB 38 A. The rise in plasma corticosterone levels was only slightly reduced by the three inhibitors. Wet dog shakes and ptosis remained unchanged. These results indicate that during the morphine withdrawal syndrome in rats there is a tonic or/and naloxone evoked release of opioid peptides, presumably enkephalins, into the periaqueductal gray matter and that inhibition of their degradation strongly decreases the severity of the withdrawal syndrome.

Analgesics↗
PubMed1986

Behavioral and physiological effects associated with changes in muscarinic receptors following administration of an irreversible cholinergic agonist (BM 123).

Previous work in our laboratory has shown that the aziridinium ion of BM 123 (N-[4(2-chloroethylmethylamino)-2-butynyl]-2 pyrrolidone) is a potent and selective muscarinic agonist and binds irreversibly to muscarinic receptors (mAChR). The present series of experiments was designed to study the effects of BM 123 on behavioral and physiological variables known to be sensitive to manipulations of the cholinergic neurotransmitter system. BM 123 was injected into the tail vein of Sprague-Dawley rats, reducing mAChR to approximately 10% of normal as judged by [3H](-)QNB binding. Oxotremorine was injected IV for purposes of comparison. Behavioral and physiological variables were measured daily for 26 days. Physiological variables (e.g., tremor, chromodacryorrhea, salivation, and temperature) showed effects in less than 5 min after injection and returned to their pretreatment baselines within minutes. Nociceptive thresholds, dependent on sensory-perceptual processes, showed peak changes of approximately +230% and returned to normal within hours. Motoric responses, i.e., drinking and general activity, recovered in 3-4 days. Learned responses and those requiring temporal discrimination took 8-11 days to recover and were the only responses paralleling the return of the mAChRs to their normal levels. Changes elicited by oxotremorine recovered more rapidly than those elicited by BM 123. The results suggest that the different variables measured are dependent on different densities of functional receptors. Implications for a theoretical model are discussed.

Animals↗
PubMed1980

The mast cells of the mammalian central nervous system. V. The effect of compound 48/80 on the neurolipomastocytoid cells and related areas of the CNS: early changes.

The response of the neurolipomastocytoid cells (NLMs) and elements in their vicinity within the central nervous system of various animal species was studied following injection of the animals with the specific mast cell (MC)-discharger compound 48/80. The observed alterations were grouped into those occurring early (0--21 days) and later (up to 18 months). In the present report, only the acute changes are described, light and electron microscopically. Most experimental animals developed prostration, scratching, acral-type reaction, signs of respiratory distress and salivation, and, in the monkey, uncontrollable somnolence. Within about 2 weeks after the injection some animals (especially guinea pigs) manifested various degrees of limb paralysis. The NLMs, like MCs outside the CNS, responded to injection by various degrees of degranulation, vacuolation, marked variation in granule size, apparent cell loss and sometimes an increase in number. Electron microscopically, particulate breakdown products of the granules of the NLMs appeared in the cytoplasm; occasionally there was suggestive evidence that they had passed inward across the vessel wall to reach the lumen, and also outward through the outermost basal lamina. Perivascular astrocytic feet showed swelling and vacuolation shortly after the injection, which was followed by evidence of gliosis and later scarring; occasionally, alterations in the mitochondria were observed. In the spinal cord of the guinea pig, capillary neoformation was observed with endothelial cells and adjacent NLMs taking up tritiated thymidine. The discussion centers on the partial similarity of response to compound 48/80 of the NLMs to that of MCs outside the CNS, and the probable involvement of NLM-damage in the parenchymal changes.

Animals↗
PubMed1986

Esophageal dischalasia: serendipity during 99mTc thyroid scan.

It is rare for a large amount of pooled radioactive saliva to be observed in the neck during a thyroid scan. Such a finding would imply abnormal salivation and/or esophageal kinesis. The case of esophageal dischalasia reported here suggests that a complete study of the esophagus is advisable when a large area or amount of radioactive saliva is observed in the neck during a thyroid scan.

Adult↗
PubMed1988

Acute inhalation toxicity of eugenol in rats.

The acute toxicity of inhaled eugenol was assessed by exposure of three groups of five male and five female rats to a submicron aerosol of eugenol for 4 h followed by a 14-day observation period. A fourth group, also of five male and five female rats and exposed to air only under similar conditions, served as a control group for comparison. The three concentrations of eugenol to which the different groups were exposed were 2.58, 1.37 and 0.77 mg/l. The mass median aerodynamic diameters and geometric standard deviations of the aerosols were, respectively, 0.82 micron (sigma g 2.26), 0.88 micron (sigma g 2.05) and 0.9 micron (sigma g 1.87). Clinical signs observed during exposure consisted principally of moderately increased salivation and restlessness (indicative of irritation) and abnormal breathing patterns. The signs were graded, being less marked in animals exposed to the lower concentrations of eugenol. All three groups, exposed to high, medium and low levels of eugenol, lost weight overnight following exposure. Associated with the weight loss were marked reductions in food and water intake. The responses appeared to be largely independent of the concentration of eugenol inhaled, although there was some evidence of a graded effect on water intake. There was rapid recovery, with food and water consumption data comparable with control values throughout most of the remainder of the 14-day observation period. Also, by the end of the observation period, group mean body weights were comparable. Upon sacrifice and macroscopic examination of the animals, abnormalities were detected in the lungs only of a few animals: 3/10 control, 2/10 eugenol 2.58 mg/l, and 2/10 eugenol 0.77 mg/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1992

Relationships between plasma composition and parotid salivary composition and secretion rates in the potoroine marsupials, Aepyprymnus rufescens and Potorous tridactylus.

Parotid salivation was investigated in two species of potoroine marsupial, Aepyprymnus rufescens and Potorous tridactylus to ascertain flow rates and composition, the buffer capacity of the saliva with respect to possible dependence of these animals on foregut fermentation, and the similarity of anion excretion patterns to those of the kangaroo parotid. Under anaesthesia neither species secreted spontaneously and secretion was stimulated by intravenous infusion of carbachol, bethanechol and isoprenaline. Under cholinergic stimulation in Aepyprymnus, the concentrations of Na, Cl, HCO3 and osmolality were positively correlated with flow rate, whereas K, Mg, PO4, H+ and urea were negatively correlated with flow. Amylase activity and the concentrations of protein and Ca showed no consistent relation to flow. Relative to Aepyprymnus, saliva of Potorous had much lower amylase activity and amylase activity per gram protein, lower concentrations of urea and Ca, and higher Na. Protein, K and HCO3 concentrations were similar in both species. The plasma of both species had similar electrolyte concentrations, but Potorous had lower protein, urea, osmolality and amylase activity. Plasma amylase activity in Aepyprymnus rose during cholinergic stimulation to levels in excess of rodent plasma. Isoprenaline infusion in Aepyprymnus increased salivary amylase activity and concentrations of protein, Ca, HCO3 and PO4, and reduced the concentrations of Cl and H+. The patterns of anion excretion in the two potoroine marsupials were dissimilar to those of the kangaroo parotid suggesting that parotid fluid secretion is not HCO3 driven to the same extent as that of Kangaroos. Buffer anion concentrations and secretion rates were similar to koalas and low relative to kangaroos, indicating that these potoroines do not rely on foregut fermentation.

Amylases↗
PubMed1986

Behavioral and physiological effects of an aziridinium analog of oxotremorine (BM130).

When injected IV BM130, a mustard analog of oxotremorine, acts initially as a cholinergic agonist and thereafter produces a sustained resistance to muscarinic agonists. Control subjects were injected with saline or with BM130A, the active aziridinium intermediate of BM130. Acute injections of BM130 were followed initially by effects that were characteristically cholinomimetic in nature: e.g., tremor, chromodacryorrhea, salivation, hypothermia. The effects were dose-dependent and of limited duration. They were not seen in behavioral variables measured 30 min after drug treatment. Injection of BM130A produced peripheral, but not central effects; saline had no effects. The prediction that initial cholinomimetic effects should be followed by sustained resistance to cholinergic agonists was tested by subjecting animals to oxotremorine challenges at weekly intervals following single injections of BM130. In none of the measures taken did animals injected with BM130A or saline show resistance to the muscarinic challenges. Those administered BM130 showed resistance, which in some variables was sustained for 3-4 weeks. The resistance was statistically significant at high BM130 doses and appeared to be dose dependent over the range studied.

Animals↗
PubMed1990

Acute autonomic and sensory neuropathy: a case report.

A female patient with acute autonomic and sensory neuropathy is described. Urinary disturbance developed rapidly and was followed by orthostatic syncope, absence of lacrimation, salivation and sweating, and sensory impairment. Muscle strength had been consistently normal despite diffuse muscular atrophy. Marked decrease in the number of small myelinated and unmyelinated fibres was revealed in biopsied sural nerve. Eighteen months after the onset, her autonomic symptoms have partially improved.

Acute Disease↗
PubMed1976

Therapeutic effects of some cholinolytics in organophosphate intoxications.

The therapeutic effects of pipethanate (sycotrol) and two newly synthetized cholinolytics, DPX-8 and ANC-51, were compared with atropine in mice poisoned by DDVP, fluostigmine, phospholine, and paraoxon. The antagonistic activotagonistic activity of tested drugs against acetylcholine-induced contraction of rat ileum and oxotremorine-induced salivation and tremor in the mouse was also studied. The anticholinergic activity of pipethanate, DPX-8, and ANC-51 was weaker than that of atropine. However,the therapeutic effect of pipethanate was higher than that of atropine in mice poisoned by the organophosphates. DPX-8 and ANC-51 afforded a better antidotal effect than atropine only in DDVP-poisoned mice.

Animals↗
PubMed1986

Amitriptyline and oxaprotiline in the treatment of hospitalized depressive patients. Clinical aspects, psychophysiology, and drug plasma levels.

Amitriptyline (AT) and the noradrenaline reuptake inhibiting antidepressant oxaprotiline (OT = hydroxymaprotiline) were compared in 59 primary depressive inpatients in a 4-week double blind parallel group design. In the Hamilton Depression Rating Scale and 2 self-rating scales AT proved to be more efficient than OT, mainly with respect to disturbances of appetite and sleep. Agitated patients receiving OT needed more additional tranquilizing medication. The number of side-effects did not differ. Both drugs increased heart rate and skin resistance level (SRL) to about the same degree and did not influence the number of spontaneous fluctuations of SRL, habituation of SRL orienting responses (OR), frequencies of respiration and blinking. Salivation was temporarily more impaired by AT. All physiological variables differed between patients and 30 healthy controls during the whole 4-week trial. Clinical outcome showed a linear relation to OT plasma levels. For AT a therapeutic window was confirmed for concentrations of AT and its metabolite nortriptyline between 125 and 200 ng/ml. Patients whose SRL-OR habituated rapidly had a better outcome than slow habituators. Urinary excretion of 3-methoxy-4-hydroxyphenylglycol was lower in patients than in controls but could not predict outcome with either drug.

Amitriptyline↗
PubMed1978

Comparative effects of cocaine and pseudococaine on EEG activities, cardiorespiratory functions, and self-administration behavior in the rhesus monkey.

The effects of cocaine and pseudococaine on the EEGs, heart and respiratory rates, and self-administration behavior were studied in rhesus monkeys. An intravenous injection of cocaine (2.5 and 4.0 mg/kg) in the monkey produced low-voltage fast waves (LVFWs) in the EEGs and behavioral hyperexcitation accompanied by marked increases in the heart and respiratory rates with mydriasis and excessive salivation. In contrast, pseudococaine produced high-voltage slow waves (HVSWs) in the EEGs and behavioral depression accompanied by the same symptoms of the autonomic functions as those produced by cocaine. Both isomers were self-administered by the monkeys. During cocaine self-administration sessions, the animals showed hyperexcitation in their overall behavior, while with pseudococaine they showed almost normal behavioral responses. These results suggest that cocaine produced excitatory effects and pseudococaine inhibitory effects on the EEGs and behavior. Both isomers stimulate the heart and respiratory rates, and were self-administered by the monkeys.

Animals↗
PubMed1995

Oropharyngeal dysphagia due to iatrogenic neurological dysfunction.

Oropharyngeal dysphagia due to iatrogenic neurological dysfunction may relate to either medication side effects or surgical complications. There are several general mechanisms by which neurological side effects of medications can cause or aggravate oropharyngeal dysphagia. These include decreased level of arousal, direct suppression of brainstem swallowing regulation, movement disorders (dyskinesias, dystonias, and parkinsonism), neuromuscular junction blockade, myopathy, oropharyngeal sensory impairment, and disturbance of salivation. Postsurgical oropharyngeal dysphagia due to neurological dysfunction has been described in association with carotid endarterectomy, esophageal cancer surgery, anterior cervical fusion, and ventral rhizotomy for spasmodic torticollis. A potential explanation for oropharyngeal dysphagia following these surgical procedures is intraoperative mechanical disruption of the innervation of the pharyngeal constrictor muscles by the pharyngeal plexus. Posterior fossa and skull base surgery can lead to dysphagia as a result of intraoperative damage to brainstem centers and/or cranial nerves involved in swallowing. Perioperative stroke is the most likely explanation for oropharyngeal dysphagia appearing acutely following surgery, especially if the type of surgery predisposes to embolism or hypoperfusion.

Anticonvulsants↗
PubMed1977

Anorexigenic and ancillary actions of MK-212 (6-chloro-2-(1-piperazinyl)-pyrazine; CPP).

In rats allowed to eat for 2 h/day and injected i.p. 30 min before feeding, MK-212, ED50 = 1.5 mg/kg, was two times more potent as an anorexigen than fenfluramine. However, the compounds were equiactive in the rat following p.o. administration 1.5 or 3 h before the test, while fenfluramine was more potent if the interval was extended to 6 h. In cats permitted to eat for 3 h/day, the ED50 dose (mg/kg p.o.) for MK-212 determined at 0.5, 1 and 3 h after feeding was, respectively, 15, 10, and 3 times less than that of fenfluramine. Emesis and diarrhea were frequently observed ancillary effects in cats treated with fenfluramine, whereas apparent sedation and salivation were commonly detected in animals after MK-212. In rats or cats pretreated with methergoline, the decrease in food consumption elicited by MK-212 was markedly inhibited, suggesting that the mechanism of action involves a serotoninlike effect. Compared with the marked stimulant action of amphetamine, MK-212 had only a minor and inconsistent effect on motor activity in rats and mice. Similar results were obtained with fenfluramine. MK-212 was not self-administered by rats, while the self-administration of amphetamine and morphine were demonstrated using the same experimental protocol.

Animals↗
PubMed1982

Reinforcing properties of clonidine in rhesus monkeys.

Intravenous clonidine self-administration was studied in rhesus monkeys under conditions of limited and unlimited access. Limited access consisted of daily 2-h experimental sessions with drug available on a fixed ratio 10 schedule. For unlimited access, drug was available 23 h/day with each response resulting in an injection. In all animals under both conditions, responding was maintained at levels that were above those maintained by saline injections at doses between 0.3 and 10 microgram/kg/inj, and the number of injections taken per session depended upon the dose. Under conditions of limited access, peak self-administration rates varied between animals but averaged approximately 30 inj/session. Total session intake was occasionally in excess of 1.0 mg/kg. Under conditions of unlimited access animals frequently self-administered more than 300 inj/day and intakes averaging 3.6 mg/kg/day occurred at the highest dose tested (10 microgram/kg/inj). When saline was substituted for clonidine after periods of clonidine access that ranged from 10-40 days, withdrawal signs included facial flushing, refusal of preferred food, restlessness, salivation, and emesis. These signs could be reversed with IV clonidine but could not be reliably precipitated with IV naloxone.

Animals↗
PubMed1978

Achalasia sicca--juvenile Sjögren's syndrome with achalasia and gastric hyposecretion.

Sjögren's syndrome (SS) in its classical form, which includes keratoconjunctivitis sicca, xerostomia and recurrent enlargement of the salivary glands, is associated with a connective tissue disease in at least half the patients. According to the present study of three patients with SS, achalasia and gastric hyposecretion seem to be either further manifestations of SS, or separate phenomena associated with SS. The gastric hyposecretion involves both the hydrochloric acid and the total volume of the secretion, but the gastric mucosa has a normal appearance on microscopy. Because of the simultaneous presence of achalasia, gastric hyposecretion and reduced salivation, we have called the combination "achalasia sicca". The reduction in the secretions of the upper gastrointestinal tract might have a pathogenic association with achalasia.

Adolescent↗
PubMed1989

Cholinergic dysfunction of heart, pupil, salivary glands, and urinary bladder in healthy volunteers during long-term treatment with clomipramine.

Cholinergic functions were studied in ten non-depressed healthy volunteers who were treated with 50 mg clomipramine daily for 3 weeks and subsequently with 100 mg daily for a further 3 weeks. Impairments in heart rate variation (HRV) at rest and standing, of the pupillary light response and of salivation were related to serum levels of clomipramine. Since reduction of HRV is closely related to dose (r = -0.83, P less than 10(-2] and is a better predictor of serum levels than the other measures examined, it is suggested that the easy obtainable function test of HRV at standing can be used as an estimate of over-all cholinergic dysfunction during treatment with tricyclic antidepressants.

Adult↗
PubMed1975

Effects of arecoline and cholinesterase inhibitors on cyclic guanosine 3',5'-monophosphate and adenosine 3'.5'-monophosphate in mouse brain.

In mice, Arecoline in vivo dose-dependently increased the cGMP concentrations of the cerebellum and the "cereberum" (= parts of cortex, hippocampus, hypothalamus, thalamus, striatum and midbrain) without influencing thecAMP levels. The cholinesterase inhibitors paraoxon and physostigmine caused an elevation only in "cerebrum", whereas the cGMP content of the cerebellum even decreased. Pretreatment with atropine prevented the rise in cGMP levels as well as the symptoms of cholinergic stimulation elicited by arecoline or paraoxon. Diazepam reduced cGMP levels below control values and blocked the effect of arecoline, while typical symptoms due to arecoline, e.g., tremor and salivation remained unaffected. The tripeptide prolyl-leucyl-glycinamide (MIF) had no effect on either cGMP values or the peripheral signs of cholinergic stimulation elicited by arecoline. The results show that elevation of cGMP in the central nervous system caused by cholinomimetic agents can be prevented not only by cholinolytics, blocking muscarinic receptors but also by influencing other mechanisms to be discussed.

Animals↗