Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Effects of arecoline and cholinesterase inhibitors on cyclic guanosine 3',5'-monophosphate and adenosine 3'.5'-monophosphate in mouse brain. 24 44

Tetrahydroaminoacridine (THA) and metrifonate are cholinesterase inhibitors used in the treatment of Alzheimer's disease. In experimental animals they inhibit acetylcholinesterase activity and have been reported to increase levels of brain acetylcholine. This paper presents results from studies of their effect at two dose levels on the dynamics of acetylcholine in mouse brain. Metrifonate at two doses (10 and 30 mg/kg intraperitoneally), known to cause cholinesterase inhibition, had no effect on levels of acetylcholine or choline or on the rate of synthesis of acetylcholine. THA (3 mg/kg intraperitoneally) had no effect on levels of acetylcholine and choline but had a shortlasting decreasing effect on the synthesis rate of acetylcholine. THA (10 mg/kg intraperitoneally) increased levels of acetylcholine and choline and markedly decreased the synthesis rate of acetylcholine. At this dose, the animals showed severe cholinergic effects, e.g. tremor and salivation. It is suggested that a moderate cholinesterase inhibition in brain facilitates cholinergic nerve transmission which is obtained at a broader dose range for metrifonate than for THA.
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PMID:Metrifonate and tacrine: a comparative study on their effect on acetylcholine dynamics in mouse brain. 143 50

A comprehensive symptomatological observational battery in conjunction with acute toxicity testing, evaluated with the method of a hyperbolic curve relating survival time (T) to dose (D), was used to characterize quantitatively the lethal toxicities of the organophosphorus (OP) compound, sarin, in mice. The experimental data observed with sarin (0.4-4.0 mg/kg s.c.), alone or in combination with atropine (ATR) (20 mg/kg i.p.), were plotted as a graph of D/T against D, a linearizing transformation of the hyperbolic function. This linearized plot gave two straight lines, deflecting at 1.2 mg/kg, in terms of latency to whole body tremor (BT) and loss of the righting reflex (LR). At lower lethal doses of sarin (0.4-1.2 mg/kg) with ATR pretreatment, the D/T vs. D curves of BT and LR were shifted in parallel to the left, while at high lethal doses (1.6-4.0 mg/kg) these curves interpolatedly converged. The sequelae and/or severity of symptoms were also comparatively different between the range of lower and high lethal doses as noted above. It has been claimed that the protective actions of ATR and clonidine (CLD) against the lethal effects of cholinesterase inhibitors are associated with different underlying mechanisms, i.e. presynaptic versus post-synaptic cholinergic inhibition. The protective effects of a single dose of ATR (20 mg/kg) and CLD (1.0 mg/kg), after 38 and 15 min of intraperitoneal pretreatment, respectively, alone or in combination, challenged with 2 x, 4x and 8x LD50's of sarin were also comparatively evaluated. ATR resulted in a nonsignificant increase in latency to onset of BT and LR. CLD significantly delayed the onset of these symptoms against all 3 dose levels of sarin intoxication, whereas ATR plus CLD additively increased the latency to the onset of these symptoms. The present results indicate that at lower dosages of sarin (less than or equal to 4 x LD50's) its mode of action appears to be mediated mainly by a/muscarinic mechanism, whereas at high doses it is mediated by some other non-specific actions superimposed on the cholinergic actions of sarin. The present study also lends support to the hypothesis of the existence of different forms of OP intoxication on the strength of lethal exposure. The possible mechanisms of both sarin lethality and ATR- and CLD-mediated protection are briefly discussed.
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PMID:A symptomatological assessment of organophosphate-induced lethality in mice: comparison of atropine and clonidine protection. 201 78

1. The effect of tetrahydroaminoacridine (THA) on cholinergically mediated behaviour in the rat and mouse has been investigated. In addition the actions of this compound on cholinesterase activity and on muscarinic and nicotinic receptors has also been examined. 2. Administration of THA (5-20 mg kg-1, i.p.) produced a dose-dependent increase in tremor, hypothermia and salivation in both rats and mice. A similar profile of activity was seen following physostigmine (0.1-0.6 mg kg-1) administration. 3. THA was approximately fifty fold less potent than physostigmine in inducing behavioural change but its effects persisted for over twice as long as those of physostigmine. For example THA-induced hypothermia was still present at 4 h in the mouse and 8 h in the rat. 4. In vitro THA was a potent non-competitive inhibitor of rat brain cholinesterase (IC50: 57 +/- 6 nM) and bovine erythrocyte acetylcholinesterase (IC50: 50 +/- 10 nM) but was a more potent inhibitor of horse serum butyrylcholinesterase (IC50: 7.2 +/- 1.4 nM). 5. Radioligand binding studies indicated that THA binds non-selectively but with moderate potency to both M1 (Ki: 600 nM) and M2 (Ki: 880 nM) muscarinic receptors. THA also interacted with the allosteric site present on cardiac M2 receptors. 6. It is concluded that THA is a reversible non-competitive inhibitor of cholinesterase with a long half life (compared with physostigmine). It also may antagonize muscarinic receptors at high doses. The long half life may account for its reported efficacy in the treatment of Alzheimer's disease.
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PMID:The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro. 280 55

Male mice were treated orally with the organophosphorus insecticides fenamiphos and dichlorvos at 10 and 150 mg/kg, respectively. The insecticides produced signs of toxicosis characteristic of cholinesterase inhibition, and induced death in all treated mice. Pretreatment of mice with diphenhydramine HCl (20 and 30 mg/kg, subcutaneously) 15 min before either insecticide significantly (P less than 0.05) reduced the incidence of toxic manifestations (excessive salivation, Straub tail, and whole body tremor), delayed the onset of death, and increased the percentage of survivors. Doses of diphenhydramine less than 20 mg/kg were not so effective. The data indicated a protective property of diphenhydramine against organophosphorus insecticide-induced toxicosis.
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PMID:Effect of diphenhydramine on organophosphorus insecticide toxicity in mice. 281 94

Propranolol in low doses antagonized and in higher doses facilitated oxotremorine-induced tremor (Oxo-tremor) in mice. Atropine blocked Oxo-tremor, an effect that was reversed by propranolol. Atropine pretreatment also antagonized the potentiating effect of propranolol on Oxo-tremor. Propranolol inhibited mice brain cholinesterase at doses which enhanced Oxo-tremor. Timolol and sotalol produced a dose-dependent antagonism of Oxo-tremor, whereas practolol failed to produce a similar effect. None of these three agents produced any significant enhancement of Oxo-tremor. These results suggest the involvement of a peripheral mechanism for the antagonism and a central cholinergic mechanism for the facilitation of Oxo-tremor by propranolol.
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PMID:Cholinergic involvement in the modulation of oxotremorine-tremor in mice by propranolol. 286 35

Twenty years after its discovery, the beta-adrenergic blocking agent propranolol continues to interest pharmacologists and clinicians. Its therapeutic profile has extended to areas beyond the purview of the cardiovascular system, and its ocular and central nervous system effects have been well documented. In addition, it still remains a very good pharmacological tool to map out the adrenergic beta-receptors in the body, and stereoisomers of propranolol and other beta-blockers serve as valuable agents to distinguish between the effects related to beta-adrenoceptors and those which are not. The primary purpose of this review is to summarize the evidence indicating that beta-adrenergic blocking agents lack stereoselectivity in some of their effects, including several of considerable therapeutic importance. Because many pharmacological actions of propranolol followed a nonsteroselective pattern, the involvement of beta-adrenoceptors in them was questioned and this led to the search for alternate mechanisms to explain these effects. Studies with propranolol and some related drugs indicated the involvement of a cholinergic mechanism in their antiarrhythmic, ocular hypotensive and some central effects. Also, a presynaptic inhibitory effect at the skeletal neuromuscular junction has been suggested to explain the benefical effect of propranolol and other beta-blockers in tremor. Biochemical studies with these drugs revealed their inhibitory action on the cholinesterase enzyme in blood and other tissues like myocardium and brain. It is thus hypothesized that modulation of cholinergic neurotransmission by propranolol could explain some of its nonstereoselective actions and open new vistas in propranolol pharmacodynamics.
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PMID:Nonstereoselective aspects of propranolol pharmacodynamics. 303 May 22

The spinal cord is capable of initiating a significant and long-lasting pressor response following intrathecal injection of cholinergic agonists in freely moving rats. The magnitude of the pressor response to the cholinesterase inhibitor, neostigmine, was greatest when the site of injection was restricted to the thoracic level. Intrathecal (i.t.) injection of neostigmine (1-10 micrograms) elicited a dose-related increase in mean arterial pressure of up to 45 mm Hg which remained elevated for almost 2 h. Significant inhibition of acetylcholinesterase was localized to the spinal cord, with the thoracic region exhibiting the greatest degree of inhibition. Also, depletion of spinal acetylcholine levels following i.t. injection of hemicholinium-3 (HC-3) resulted in a significant reduction in the magnitude of the neostigmine-induced pressor response. Carbachol, a direct-acting cholinergic receptor agonist also increased mean arterial pressure following i.t. injection. However, the pressor response to carbachol was not reduced following HC-3. For both agonists, cardiovascular changes were accompanied by significant behavioral changes characterized by tremor, scratching, tail biting and chewing. The appearances of these behaviors following neostigmine injection were reduced in frequency and intensity in HC-3-pretreated animals. These findings demonstrate the ability of spinal cholinergic neurons to mediate a significant hypertensive response. The presence of marked behavioral changes accompanying the cardiovascular response suggests the possibility that cholinergic neurons may be part of an ascending spinal system.
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PMID:Hypertension following intrathecal injection of cholinergic agonists in conscious rats: role of endogenous acetylcholine. 322 83

Atropine, a postsynaptic muscarinic antagonist, and clonidine, a presynaptic inhibitor of acetylcholine release, protect mice from the lethal effects of soman, a potent and irreversible cholinesterase inhibitor. The purpose of this study was to determine the effects of atropine (6 mg/kg) and clonidine (0.2 mg/kg) on soman-induced lethality and behavioral changes in the rat. Soman produced a dose-dependent increase in lethality over a narrow concentration range (50-200 micrograms/kg, SC). Soman produced time- and dose-dependent increases in tremor, salivation, hind limb extension, convulsions and chewing behaviors, as well as decreases in three normal stereotyped behaviors, sniffing, locomotion and rearing. Atropine and clonidine were equally effective at limiting soman-induced lethality and behavioral changes. The protective effects of clonidine and atropine were synergistic, even though clonidine antagonizes some of the stereotyped behaviors elicited by atropine. Simultaneous pretreatment with clonidine and atropine completely eliminated the lethality and behavioral changes produced by injection of 200 micrograms/kg soman.
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PMID:Behavioral effects of toxic doses of soman, an organophosphate cholinesterase inhibitor, in the rat: protection afforded by clonidine. 336 26

The influence of clonidine on the toxicity produced by two irreversible, organophosphate cholinesterase inhibitors, soman and echothiophate, was studied in mice. At lethal doses, soman produced whole body tremor but no muscle fasciculation; at lethal doses, echothiophate produced muscle fasciculations but no whole body tremor. Pretreatment with clonidine protected against several toxic manifestations of soman, but had little effect on echothiophate toxicity. In addition to its documented effects on acetylcholine metabolism, clonidine was found to be a weak inhibitor of acetylcholinesterase. At certain concentrations, clonidine protected the enzyme from permanent inactivation by soman. These findings indicate that the toxicity of soman and echothiophate reflect primarily central and peripheral actions, respectively, and that clonidine has a much greater protective effect versus the centrally-acting agent. Moreover, direct interactions with acetylcholinesterase may contribute to clonidine protection from cholinesterase inhibitor toxicity.
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PMID:Clonidine protection from soman and echothiophate toxicity in mice. 378 71


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