Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020672 (hypothermia)
17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study sought to assess whether the compound N-[4-(2-chloro-ethylmethylamine)-2-butynyl]-2-pyrrolidone (BM123), a potent muscarinic agonist that binds irreversibly to the muscarinic receptor (mAChR), has long-lasting functional effects which may be related to a reduction in functional mAChRs. Passive (inhibitory) avoidance performance, one-way active avoidance learning, and spontaneous alternation behavior were studied in rats. The results confirmed the acute muscarinic stimulating effects of BM123, including tremor, salivation, chromodacryorrhea and hypothermia. In addition, when measured 3-4 days after administration, rats treated with BM123 had disrupted spontaneous alternation performance and tended to have impaired performance for the inhibitory avoidance task with facilitated acquisition of active avoidance. This spectrum of effects is consistent with previous reports showing a 20-40% reduction in mAChRs at these times after BM123. The reversible muscarinic agonist, oxotremorine, was without significant effect. In a further experiment, it was found that pretreatment with methyl atropine did not prevent the disruption of spontaneous alternation behavior by BM123, whereas pretreatment with atropine did. Thus, these long-lasting behavioral effects of BM123 are related to its alkylation of and subsequent reduction in central mAChRs.
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PMID:Effects of an irreversible muscarinic agonist (BM123) on avoidance and spontaneous alternation performance. 324 11

To characterize the hypothermia-induced changes in the activity and kinetic constants for muscarinic receptors, we investigated the effects of hypothermia on the onset and offset of action of phenoxybenzamine from the muscarinic receptors of the longitudinal muscle of the guinea-pig isolated ileum. At 37 degrees C, the onset of phenoxybenzamine action was very rapid (less than 5 min) and there was no apparent recovery of the response to ACh 70 min after washing off the phenoxybenzamine. However, the onset at 24 degrees C was very slow (30 min) and there was a complete recovery of the response to ACh 40 min after washing off the unoccluded phenoxybenzamine. We concluded that the lack of reversibility of the effects of phenoxybenzamine at 37 degrees C is due to the predominance of covalent binding between the receptors and phenoxybenzamine whereas at 24 degrees C the blockade of the muscarinic receptor by phenoxybenzamine is mainly due to simple occlusion.
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PMID:The effects of hypothermia on the blockade of muscarinic receptors by phenoxybenzamine. 339 77

The withdrawal of tricyclic antidepressants produces symptoms characteristic of cholinergic overdrive states. The authors previously proposed that these states are the consequence of the pharmacological induction of cholinergic system supersensitivity by chronic treatment with antidepressants, combined with a reduction in the plasma level of a competitive muscarinic receptor antagonist when the dose of a tricyclic is decreased. This is consistent with the facts that all tricyclic antidepressants are antimuscarinic agents and that classical antimuscarinic compounds, such as scopolamine, up-regulate and supersensitize muscarinic cholinergic systems. The authors present evidence that chronic treatment with amitriptyline supersensitizes a central cholinergic mechanism. Core body temperature is subject to influence by a central (hypothalamic) muscarinic mechanism, which is rendered supersensitive to cholinomimetic challenge by treatment with scopolamine. The authors telemetrically measured the hypothermic responses of adult male rats to various doses of the muscarinic agonist oxotremorine before and in the course of chronic treatment with amitriptyline. Treatment with amitriptyline resulted in marked enhancement of the cholinomimetic-induced hypothermia. Methylscopolamine nitrate, a peripherally active antimuscarinic agent, did not block the hypothermic response to oxotremorine, whereas scopolamine, a centrally active antimuscarinic compound, did. This study indicates that the chronic administration of amitriptyline can produce supersensitivity of a central muscarinic cholinergic mechanism. Clinical and theoretical implications of this finding are discussed.
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PMID:Amitriptyline supersensitizes a central cholinergic mechanism. 356 63

The irreversible muscarinic agonist, BM123 (63 mu moles kg-1, IV), was shown to produce central and peripheral physiological signs characteristic of cholinergic agonists. It also induced hypothermia, elevated nociceptive thresholds, reduced locomotor activity and disrupted spontaneous alternation performance in rats. The centrally acting muscarinic antagonist, atropine (50 mu mole kg-1) prevented or reduced all the above effects of BM123 when given SC 40 min prior to the BM123 injection. In contrast, the peripherally acting muscarinic antagonist, N-methyl atropine, prevented only the peripheral effects and the elevated nociceptive thresholds. Habituation of activity during a 20 min session was observed in all groups despite different levels of general activity. These findings are consistent with a model in which atropine and N-methyl atropine compete with BM123 for reversible association with the muscarinic receptor. In the case of BM123 administered alone, the association results, first, in agonist effects and proceeds to form an irreversible complex. Our present results show that by competing with BM123 for mAChR sites during the initial, reversible state of the interaction, atropine blocks the cholinomimetic effects of the agonist during both this state and its otherwise subsequent irreversible state.
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PMID:Influence of atropine and N-methyl atropine pretreatments on behavioral and physiological effects of the irreversible muscarinic agonist, BM123. 357 64

Diazepam has previously been shown to affect the acetylcholine synthesizing system in mouse brain. This paper reports studies on the effect of diazepam on muscarinic receptor density and on pharmacological effects of oxotremorine. The receptor density was studied using a new technique that allows such studies to be performed in vivo under physiological conditions. The method is based on the fact that L-hyoscyamine, the active antipode of atropine, binds specifically to muscarinic receptors in the brain, and can be measured with high sensitivity by gas chromatography--mass spectrometry. Diazepam was found to modify the binding properties of muscarinic receptors in CNS, thereby decreasing the functional receptor pool. It also prevented tremor induced by the muscarinic agonist oxotremorine. Diazepam could however not prevent the hypothermia induced, but rather accentuated this effect of oxotremorine. It is concluded that diazepam, directly or indirectly, influences the effect of cholinergic stimulators by modulating the size of the muscarinic receptor pool.
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PMID:Effects of diazepam on muscarinic acetylcholine receptor binding in vivo and on oxotremorine-induced tremor and hypothermia in mice. 358 23

The effects of the compound RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide) in a number of in vitro and in vivo test systems for muscarinic cholinergic activity were analyzed and compared to those of classical muscarinic receptor agonists. In radioligand binding assays RS 86 presented high nanomolar apparent affinity only for sites labeled by 3H-muscarinic receptor agonists while its apparent affinity for sites labeled by 3H-muscarinic receptor antagonists including [3H]QNB, [3H]NMS and [3H]pirenzepine was in the micromolar range. RS 86 had no or only low affinity (IC50 greater than 10 microM) for other neurotransmitter or drug receptor sites. The compound induced scopolamine-sensitive contractions of the isolated guinea-pig ileum showing a pD2 of 6 in this model. In the isolated rat superior cervical ganglion RS 86 was also an agonist with a pD2 of 6.7. When given to mice or rats by different routes RS 86 induced central and peripheral effects typical of a muscarinic receptor agonist, such as hypothermia, tremor, mydriasis, salivation, lacrimation, diarrhoea and modification of behavior as observed in an open field. In several of these tests RS 86 was about 10 times less potent than oxotremorine but more potent than arecoline, pilocarpine, aceclidine or the compound (cis) AF-30. The ED50 values for some central effects, including the induction of hypothermia and alert non-mobile behavior were lower than those for tremor and peripheral effects. Some of the effects lasted for up to 6 h, depending on the dose. Finally, RS 86 administration resulted in modifications of brain acetylcholine turnover and high affinity choline uptake typical of a central muscarinic receptor agonist. Taken together these results demonstrate clearly that RS 86 is a potent, centrally acting, selective muscarinic receptor agonist. RS 86 appears to be an adequate tool for the clinical examination of the cholinergic hypothesis of Alzheimer's disease.
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PMID:The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide). A potent, specific muscarinic acetylcholine receptor agonist. 373 91

The present study assessed in rats the effects of muscarinic receptor antagonism upon analgesia induced by cold-water swims (CWS: 2 degrees C for 3.5 min) and 2-deoxy-D-glucose (2DG: 600 mg/kg). First, CWS analgesia was significantly reduced 30 min after the swim by scopolamine (0.01 and 0.1 mg/kg) and methylscopolamine (10 mg/kg) pretreatment, and was eliminated 60 min after the swim by scopolamine (0.01-10 mg/kg) and methylscopolamine (1,10 mg/kg) pretreatment. In contrast, scopolamine potentiated CWS hypothermia. Second, while scopolamine (1 mg/kg) and methylscopolamine (1,10 mg/kg) pretreatment prolonged 2DG analgesia, both antagonists dose-dependently reduced 2DG hyperphagia. Third, the changes in analgesic and hypothermic stress responses were not due to baseline shifts in jump thresholds or body temperatures. However the dose-dependent reductions by scopolamine and methylscopolamine in baseline food intake and 2DG hyperphagia were significantly correlated. Fourth, the dose-dependent reduction by scopolamine and methylscopolamine of pilocarpine analgesia differed in pattern from the other analgesic effects, suggesting heterogeneity in muscarinic receptor modulation of different analgesic responses.
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PMID:Effects of muscarinic receptor antagonism upon two forms of stress-induced analgesia. 374 24

Intracerebroventricular administration of dibutyryl cyclic AMP (Db-cAMP), induced hyperthermia in guinea-pigs which was not mediated through prostaglandins (PG) or norepinephrine since a prostaglandin synthesis inhibitor, indomethacin, and an alpha-adrenergic receptor blocking agent, phenoxybenzamine did not antagonize the hyperthermia. In contrast, the hyperthermic response to dibutyryl cyclic AMP was attenuated by central administration of a beta-adrenergic receptor antagonist, sotalol, indicating that cyclic AMP may be involved, through beta-adrenergic receptors, in the central regulation of heat production/conservation. Central administration of dibutyryl cyclic GMP (Db-cGMP) produced hypothermia which was not mediated via histamine H1- or H2-receptors and serotonin since the H1-receptor antagonist, mepyramine, the H2-receptor antagonist, cimetidine, and the serotonin antagonist, methysergide, had no antagonistic effects. The antagonism of hypothermia induced by dibutyryl cyclic GMP and acetylcholine + physostigmine, by central administration of a cholinergic muscarinic receptor antagonist, atropine, and not by a cholinergic nicotinic receptor antagonist, d-tubocurarine, suggests that cholinoceptive neurons and endogenous cyclic GMP may regulate heat loss through cholinergic muscarinic receptors. These results support a regulatory role in thermoregulation provided by a balance between opposing actions of cyclic AMP and cyclic GMP in guinea-pigs.
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PMID:Opposing actions of dibutyryl cyclic AMP and GMP on temperature in conscious guinea-pigs. 630 46

Central administration of galanin in the mouse dose-dependently blocked the hypothermia induced by the muscarinic receptor agonist, 2-ethyl 8-methyl-2,8-diazospiro[4,5]decan-1,3-dion hydrobromide, RS86 (minimum effective dose, MED = 3 nmol) and the acetylcholinesterase inhibitor tetrahydroaminoacridine, (MED = 3 nmol). This inhibitory effect was reversed over the dose range (0.1, 0.3, 1, 3 nmol) by the galanin receptor antagonist galantide (MED = 0.3 nmol). Furthermore, the ATP-sensitive K+ channel blockers glibenclamide (MED = 1 nmol) and gliquidone (10 nmol) both prevented the inhibitory effects of galanin on RS86 induced hypothermia. Glibenclamide (10 nmol) also reversed the inhibitory effects of galanin on tetrahydroaminoacridine induced hypothermia. Preincubation of rat cortical membranes with galanin (10 nM, 1000 nM) in vitro had no effect on binding affinity, receptor number or pharmacology of the rat cortical muscarinic receptor. In contrast to the high affinity of glibenclamide, galanin only weakly displaced [3H]glibenclamide binding in mouse whole brain homogenates (36% at 10 microM). These studies suggest that the inhibitory effect of galanin on cholinergically mediated hypothermia induced by RS86 and tetrahydroaminoacridine may be exerted via an action at ATP-sensitive K+ channels but is unlikely to be acting directly at the site labelled by [3H]glibenclamide.
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PMID:Hypothermia induced by cholinomimetic drugs is blocked by galanin: possible involvement of ATP-sensitive K+ channels. 751 82

Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1- methylpyridine] has been evaluated as a muscarinic receptor agonist. In vitro, xanomeline had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for a number of other neurotransmitter receptors and uptake sites. In cells stably expressing genetic m1 receptors, xanomeline increased phospholipid hydrolysis in CHO, BHK and A9 L cells to 100, 72 and 55% of the nonselective agonist carbachol. In isolated tissues, xanomeline had high affinity for M1 receptors in the rabbit vas deferens (IC50 = 0.006 nM), low affinity for M2 receptors in guinea pig atria (EC50 = 3 microM), was a weak partial agonist in guinea pig ileum and was neither an agonist nor antagonist in guinea pig bladder. In vivo, xanomeline increased striatal levels of dopamine metabolites, presumably by acting at M1 heteroreceptors on dopamine neurons to increase dopamine release. In contrast, xanomeline had only a relatively small effect on acetylcholine levels in brain, indicating that it is devoid of actions at muscarinic autoreceptors. In the gastrointestinal tract, xanomeline inhibited small intestinal and colonic motility, but increased small intestinal transmural potential difference. In contrast to the nonselective muscarinic agonist oxotremorine, xanomeline did not produce salivation, tremor nor hypothermia; it did, however, increase heart rate. The present data are consistent with the interpretation that xanomeline is a novel muscarinic receptor agonist with functional selectivity for M1 muscarinic receptors both in vitro and in vivo.
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PMID:Xanomeline: a novel muscarinic receptor agonist with functional selectivity for M1 receptors. 790 57


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