UMLS:C0020672 - FACTA Search

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

Downregulation of cholinergic receptors is a consequence of subchronic exposure to an organophosphate anticholinesterase. The purpose of this investigation was to determine if there was a downregulation of the cholinergic receptors in mice following administration of a single dose of soman (pinacolyl methylphosphonofluoridate) or physostigmine. The change in the temporal response (mean minimum temperature and area under the curve) of core temperature following administration of either a muscarinic or nicotinic agonist such as oxotremorine (156 micrograms/kg, IP) or nicotine hydrogen tartrate (15 mg/kg, SC) was used as an indicator of downregulation of muscarinic or nicotinic receptors, respectively. Twenty-four h following soman (100 micrograms/kg, SC) administration, there was a significant decrease (p less than 0.05) in oxotremorine- but not nicotine-induced hypothermia. The significant differences in the mean minimum temperature and AUC were still present 4 days after exposure to the soman. Neither lower doses of the organophosphate anticholinesterase, soman (50 and 70 micrograms/kg), nor the carbamate anticholinesterase, physostigmine (500 micrograms/kg), produced a significant change in either oxotremorine- or nicotine-induced hypothermia. The results of this study suggest that receptor downregulation observed after subchronic administration of soman is also evident following administration of a single, sublethal dose of an organophosphate anticholinesterase, soman, but not after administration of a carbamate anticholinesterase, physostigmine. The in vivo assessment of the muscarinic receptor using oxotremorine hypothermia may be a sensitive indicator of the functionality of the drug-receptor coupling and indicate a physiological consequence of receptor downregulation.
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PMID:Effect of a single dose of an acetylcholinesterase inhibitor on oxotremorine- and nicotine-induced hypothermia in mice. 176 13

Effect of some selective agonists and antagonists of cholinergic M receptor subtypes on rectal temperature was investigated in rats at an ambient temperature of 25 degrees +/- 2 degrees C. Centrally administered acetylcholine (ACh) induced transient hypothermia, whereas the muscarinic M1 receptor agonists, arecholine (ip) and McN-A-343 (McN) (icv), induced sustained and dose-related hypothermia. However, the nonspecific muscarinic receptor agonist, oxotremorine, and physostigmine, induced hypothermia at a lower dose and hyperthermia, accompanied by tremors, at higher doses. The muscarinic M2 receptor agonist, carbachol (icv) also produced a dose-related dual effect, hyperthermia and hypothermia being induced by the lower and higher doses, respectively. The M1 receptor antagonists, scopolamine (ip) and pirenzepine (icv), induced hyperthermia, whereas the M2 receptor antagonists, gallamine (icv) and AF-DX 116 (AFDX) (ip), produced hypothermia. The hypothermic effects of ACh. arecholine, McN, physostigmine, oxotremorine and carbachol were attenuated by scopolamine and pirenzepine. However, although scopolamine also inhibited the hyperthermic and tremorogenic effects of the higher dose of oxotremorine, it had a synergistic effect with the hyperthermia-inducing higher dose of physostigmine. AFDX attenuated the hyperthermic effect of the lower dose of carbachol, indicating that it was M2 receptor-mediated. Hemicholinium, an ACh synthesis inhibitor, had a transient hypothermic effect followed by slight hyperthermia. However, it markedly antagonized the hypothermic effects of gallamine and AFDX, indicating that their effects were dependent upon the availability of neuronal ACh. The results indicate that cholinergic hypothermia is a function of central muscarinic M1 receptors, with the M2 receptors serving as automodulators.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thermic response of selective muscarinic agonists and antagonists in rat. 186 96

Behavioral effects of organophosphates (OPs) typically decrease with repeated exposure, despite persistence of OP-induced inhibition of acetylcholinesterase (AChE) and downregulation of muscarinic acetylcholine (ACh) receptors. To characterize this tolerance phenomenon, rats were trained to perform an appetitive operant task which allowed daily quantification of working memory (accuracy of delayed matching-to-position), reference memory (accuracy of visual discrimination) and motor function (choice response latencies and inter-response times during delay). Daily s.c. injections of 0.2 mg/kg of diisopropylfluorophosphate (DFP) caused no visible cholinergic signs, did not affect body weight or visual discrimination, but progressively impaired matching accuracy and lengthened response latencies and interresponse times. These effects recovered in seven of eight treated rats after termination of DFP treatment. Resumption of daily DFP at 0.1 mg/kg caused smaller impairments of both matching accuracy and response latency. After 21 injections of 0.2 mg/kg/day of DFP, rats were subsensitive to the hypothermia induced by acute oxotremorine (0.2 mg/kg i.p.), as expected after OP-induced downregulation of muscarinic ACh receptors. Evidence for supersensitivity to scopolamine (0.03 and 0.056 mg/kg i.p.) in DFP-treated rats was mixed, with additive effects predominating on both the cognitive and motor aspects of the task. After 18 days of 0.1 mg/kg of DFP, AChE was inhibited 50 to 75% and muscarinic ACh receptor density was reduced 15 to 20% in hippocampus and frontal cortex. Progressive declines in AChE activity in hippocampus and frontal cortex across 15 daily doses with DFP at 0.1 and 0.2 mg/kg were observed in other rats; quinuclidinyl benzilate binding was significantly reduced in hippocampus after 15 doses at both levels of DFP. These results indicate that animals showing a definitive sign of tolerance to OP administration (subsensitivity to a cholinergic agonist) were also functionally impaired on both the mnemonic and motoric demands of a working memory task. The nature of this impairment suggests further that it results from compensatory changes in the central nervous system, e.g., muscarinic receptor downregulation, considered to produce "tolerance" to OPs in exposed animals.
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PMID:Behavioral and neurochemical changes in rats dosed repeatedly with diisopropylfluorophosphate. 199 4

The Flinders Sensitive Line (FSL) was derived from the Sprague-Dawley rat by selectively breeding those animals exhibiting a high level of sensitivity to an anticholinesterase. The Flinders Resistant Line (FRL) was simultaneously developed as a control line. These lines exhibit nonoverlapping distributions of their thermic responsiveness to oxotremorine. Bright light prevents the development of supersensitivity to oxotremorine occurring as a result of forced stress or treatment with a muscarinic receptor antagonist in the rat. The authors now report that treatment with bright light during the regular photoperiod (i.e., a time that does not produce a phase-shift or free-running) differentially affects the hypothermic response and activity-suppressing effect of oxotremorine in both the FSL and FRL. Both lines exhibit decreased hypothermia without reduction in motor activity in response to oxotremorine following 6 days of treatment with bright light. The magnitude of blunting of the hypothermic response was greater in the FSL than the FRL. These findings suggest that (1) studies of the effects of bright light are contingent on the end point one measures and (2) the capacity of this treatment to blunt the hypothermic response to a muscarinic agonist is greater in an animal model with endogenously hyperactive muscarinic cholinergic systems.
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PMID:Effects of bright light on responsiveness to a muscarinic agonist in rats selectively bred for endogenously increased cholinergic function. 224 91

The main aim of the present study was to investigate if responses to the direct dopamine agonist, apomorphine, could be modified by changes in the activity of cholinergic neurones. A novel approach was adopted in which these responses were assessed following reduction of muscarinic receptor concentration (mAChR) in the brain (assessed from [3H] QNB binding) by the alkylating derivative of oxotremorine, N-[4-(2-chloroethylmethylamino)]-2-pyrrolidone (BM 123). Stereotyped responses elicited by apomorphine were significantly reduced when QNB binding was 12% and 50% of control values. No changes in [3H] spiperone binding were found. There was significant hypothermia in the group with 12% QNB binding sites which was significantly increased by apomorphine. Body temperature returned to normal when QNB binding was 50% of control values. There was a significant decrease in activity when QNB sites were reduced to 12% of normal and vertical activity was still significantly reduced at 50% QNB binding, though horizontal activity was not then different from controls. These data are consistent with the hypothesis that changes in the function of mAChR modify responses elicited by dopamine receptor stimulation in both the striatum and other brain regions.
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PMID:Pretreatment with an irreversible muscarinic agonist affects responses to apomorphine. 233 42

Lowering temperature from 37 degrees C to 22, 18, and 14 degrees C triggered automaticity of smooth longitudinal muscle of guinea pig isolated ileum. The amplitude of the hypothermia-induced automaticity was dependent on the degree of temperature drop: the greater the temperature drop, the greater the amplitude. However, when the preparation was initially prepared and maintained at 14 degrees C and then the temperature was raised at a similar rate to 18, 22, and 37 degrees C, the automaticity was not observed. This series of observations suggests that cooling rate may be the trigger and/or part of the triggering mechanism for the observed automaticity. Mepenzolate (1.0 x 10(-6) M), a specific muscarinic receptor antagonist, blocked the automaticity suggesting the involvement of muscarinic receptors in the pathogenesis and/or the manifestation of the automaticity. Verapamil (1.0 x 10(-7) M), a calcium channel blocker which inhibits the transmembrane Ca2+ influx into smooth muscle cells during excitation, blocked the automaticity suggesting that transmembrane Ca2+ influx plays a significant role in the pathogenesis and/or manifestation of the automaticity. A specific cytoplasmic calcium channel blocker, 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (1.0 x 10(-6) M) blocked the automaticity, suggesting that cytoplasmic calcium also plays a significant role in the pathogenesis and/or manifestation of the automaticity. In order to characterize the temperature-induced changes in the muscarinic receptors, an attempt was made to use the classic method of Furchgott and Burstyn to determine the dissociation constants of acetylcholine at muscarinic receptors at different temperatures. However, the alkylation of muscarinic receptors with phenoxybenzamine at lower temperatures was erratic and the recovery from the occlusion was too rapid to apply the method of Furchgott and Burstyn. We concluded that the lack of reversibility of the effects of phenoxybenzamine at 37 degrees C is due to the predominance of covalent bonding of phenoxybenzamine with the receptors, whereas at lower temperatures like 24 degrees C, the blockade of the muscarinic receptors by phenoxybenzamine is mainly due to simple occlusion.
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PMID:Low temperature and muscarinic receptor activities. 279 13

Hypothermia has previously been demonstrated to induce supersensitivity (defined as a decrease in the ED50) of guinea pig left atria to the negative inotropic effect of carbachol. In the present investigation, the dissociation constant (pKA or -log KA) for carbachol, determined using benzilylcholine mustard, was found to be significantly increased at 25 degrees C compared to 37 degrees C. However, the increase in pD2 (-log ED50) for carbachol at 25 degrees C was much less than would be predicted from the increase in pKA. Increasing the extracellular Ca2+ concentration or the frequency of stimulation, both of which, like hypothermia, are believed to increase Ca2+ influx into cardiac cells, resulted in a decrease in sensitivity to carbachol. Carbachol had no significant effect on cAMP or cGMP levels at either 37 degrees C or at 25 degrees C. These results suggest that the hypothermia-induced increase in sensitivity of left atria to carbachol can be explained by an increase in the affinity of the muscarinic receptor for this agonist. However, the expression of this increased affinity appears to be limited. This may be due to a concurrent decrease in the efficacy of the carbachol muscarinic receptor complex.
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PMID:The mechanism of hypothermia-induced supersensitivity of guinea pig left atria to carbachol. 285 62

The enantiomers of three 5-methyl-2-pyrrolidone analogues of the muscarinic agent oxotremorine (1) were synthesized. The pyrrolidine derivative (R)-13 was an antagonist to carbachol in the guinea pig ileum and also showed central and peripheral antimuscarinic activity in vivo. It was more potent and more selective than atropine in antagonizing the central effects of 1. The dimethylamino analogue (R)-14 and the trimethylammonium salt (R)-15 were potent agonists in the guinea pig ileum. (R)-14 showed both central muscarinic (hypothermia) and central antimuscarinic activity (antagonism of oxotremorine-induced tremor) in vivo. The R enantiomers of 13-15 were considerably more potent than the S enantiomers in vivo and in vitro irrespective of whether agonist or antagonist activity was measured. From a comparison of the contribution of the methyl group at the chiral center to the overall affinities, it is suggested that agonists and antagonists in this series bind in an essentially identical manner to the muscarinic receptor.
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PMID:Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogues. N-[4-(tertiary amino)-2-butynyl]-5-methyl-2-pyrrolidones. 293 18

Receptor plasticity is an important compensatory process by which the central nervous system adapts to pathological insult or long-term exposure to drugs. Senescent animals may show an age-related impairment of muscarinic receptor up- or down-regulation after chronic exposure to cholinergic drugs. The purpose of this study was to assess biochemical and pharmacological endpoints of muscarinic receptor plasticity in young, adult and senescent animals. Male, Fischer 344 rats (ages 3, 9, and 27 months) were administered methylatropine or oxotremorine intracerebroventricularly (IVT) for 3 weeks and tested for their functional response to a muscarinic agonist. The density of hypothalamic, muscarinic receptors was also estimated from analysis of 3H-QNB binding isotherms. In young rats, parallel changes in muscarinic receptors and response were noted, but chronic administration of cholinergic drugs to senescent animals had no effect. Thus, 3H-QNB binding in hypothalamus of young and adult rats was increased (31% and 17%) after chronic IVT methylatropine and decreased (20% and 15%) after IVT oxotremorine. Also, young rats treated with IVT methylatropine were supersensitive to the hypothermic effects of a muscarinic agonist (oxotremorine), while young and adult animals administered chronic IVT oxotremorine exhibited marked tolerance. In contrast, identically treated senescent rats showed no changes in 3H-QNB binding or oxotremorine-induced hypothermia. These results demonstrate the impaired ability of senescent rats to up- or down-regulate brain muscarinic receptors and to exhibit functional adaptations seen in young animals treated chronically with cholinergic drugs.
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PMID:Pharmacological adaptations and muscarinic receptor plasticity in hypothalamus of senescent rats treated chronically with cholinergic drugs. 314 21

Rolipram, in contrast to the tricyclic antidepressants amitriptyline and imipramine or the acetylcholine receptor antagonist atropine, failed to antagonize the salivation, hypothermia, or tremor caused in mice by the muscarinic receptor agonists pilocarpine or oxotremorine. The absence of anticholinergic activity, the extremely low therapeutic dose, and the novel mechanism of antidepressant action suggest that rolipram may also be a well tolerable antidepressant suitable for the treatment of problematic subpopulations of depressives such as elderly patients.
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PMID:Absence of anticholinergic activity of rolipram, an antidepressant with a novel mechanism of action, in three different animal models in vivo. 322 52

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