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 tremorogenic properties of a series of benzylimidoylurea derivatives are described. The most potent member, N-carbamoyl-2-(2,6-dichlorophenyl) acetamidine hydrochloride (LON-954), produces a reproducible, dose-dependent rest tremor in the mouse with oral doses of 5-100 mg/kg which is also seen in other species (rat, cat, dog, rabbit). The tremor is of constant frequency, rapid onset and short duration. It is not accompanied by akinesia, muscle ridigity, antinociceptive activity, parasympathomimetic effects or marked hypothermia and in these respects differs from tremor produced by oxotremorine. Pretreatment with a microsomal enzyme inhibitor had no effect on the tremor. An LD50 of 165 mg/kg p.o. was calculated in the mouse. After repeated administration both acute and chronic tolerance developed to the tremorogenic effects of LON-954. Evidence for a central site of action is presented, since the tremor could be reproduced following injection of small quantities (50-100 microgram) into the cerebral ventricles of the mouse. Furthermore, the use of spinal, decorticate and and decerebrate rats indicated that although tremor is not of cortical origin, it arises in an area rostral to the inferior colliculi. The mechanism underlying the tremor appears to involve dopaminergic pathways, since the action of LON-954 was antagonised by L-dopa and apomorphine and potentiated by pimozide. Atropine and carbachol were without effect. It is suggested that LON-954 could be used as an alternative to oxotremorine for the detection of anti-Parkinson drugs, particularly those exerting their effects through dopaminergic mechanisms.
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PMID:The pharmacology of N-carbamoyl-2-(2,6-dichlorophenyl)acetamidine hydrochloride (LON-954) a new tremorogenic agent. 58 44

1. An investigation of central cholinoceptors in the mouse has been made by injecting cholinomimetic drugs into the cerebral ventricles and seeing how their effects were modified by prior administration of atropine-like substances and other drugs.2. Carbachol or oxotremorine injected in small doses intracerebroventricularly into conscious mice caused hypothermia, gross tremor and a variety of parasympathomimetic effects including lachrymation and salivation. Acetylcholine injected in this way was active only in much larger doses.3. Methacholine and pilocarpine also caused a variety of parasympathomimetic effects after intracerebroventricular injection but virtually no hypothermia or tremor.4. Nicotine injected intracerebroventricularly caused mild hypothermia, fine tremor but no parasympathomimetic effects.5. Atropine-like drugs, tricyclic antidepressants and amphetamine antagonized the hypothermia induced by intracerebroventricular carbachol or oxotremorine.6. The sites of action of the atropine-like drugs are in the brain; those of the tricyclic antidepressants and amphetamine are in the periphery probably on heat generating beta-adrenoceptor mechanisms.7. It is concluded that the atropine sensitive cholinoceptors in the brain vary in their sensitivities to cholinomimetic drugs, other than acetylcholine, and may exist in isoreceptor forms.8. Peripheral atropine sensitive cholinoceptors may also exist in isoreceptor forms.
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PMID:Investigation of central cholinergic mechanisms in the conscious mouse. 558 Jun 97

Determination of muscarinic agonist-induced parasympathomimetic effects in wild type and M2 and M4 muscarinic receptor knockout mice revealed that M2 receptors mediated tremor and hypothermia, but not salivation. The M4 receptors seem to play a modest role in salivation, but did not alter hypothermia and tremor. In the M2 knockout mice, agonist-induced bradycardia in isolated spontaneously beating atria was completely absent compared to their wild type litter mates, whereas agonist-induced bradycardia was similar in the M4 knockout and wild type mice. The potency of carbachol to stimulate contraction of isolated stomach fundus, urinary bladder and trachea was reduced by a factor of about 2 in the M2 knockout mice, but was unaltered in the M4 knockout mice. The binding of the muscarinic agonist, [3H]-oxotremorine-M, was reduced in cortical tissue from the M2 knockout mice and to a lesser extent from the M4 knockout mice, and was reduced over 90% in the brain stem of M2 knockout mice. The data demonstrate the usefulness of knockout mice in determining the physiological function of peripheral and central muscarinic receptors.
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PMID:Investigations into the physiological role of muscarinic M2 and M4 muscarinic and M4 receptor subtypes using receptor knockout mice. 1139 15

Muscarinic agonist-induced parasympathomimetic effects, in vivo phosphoinositide hydrolysis and seizures were evaluated in wild-type and muscarinic M1-M5 receptor knockout mice. The muscarinic agonist oxotremorine induced marked hypothermia in all the knockout mice, but the hypothermia was reduced in M2 and to a lesser extent in M3 knockout mice. Oxotremorine-induced tremor was abolished only in the M2 knockout mice. Muscarinic agonist-induced salivation was reduced to the greatest extent in M3 knockout mice, to a lesser degree in M1 and M4 knockout mice, and was not altered in M2 and M5 knockout mice. Pupil diameter under basal conditions was increased only in the M3 knockout mice. Pilocarpine-induced increases in in vivo phosphoinositide hydrolysis were completely absent in hippocampus and cortex of M1 knockout mice, but in vivo phosphoinositide hydrolysis was unaltered in the M2-M5 knockout mice. A high dose of pilocarpine (300 mg/kg) caused seizures and lethality in wild-type and M2-M5 knockout mice, but produced neither effect in the M1 knockout mice. These data demonstrate a major role for M2 and M3 muscarinic receptor subtypes in mediating parasympathomimetic effects. Muscarinic M1 receptors activate phosphoinositide hydrolysis in cortex and hippocampus of mice, consistent with the role of M1 receptors in cognition. Muscarinic M1 receptors appear to be the only muscarinic receptor subtype mediating seizures.
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PMID:Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity. 1271 43