title: Alpha-2 adrenoceptor agonists decrease cyclic guanosine 3',5'-monophosphate in the mouse brain.
abstract: BACKGROUND
  In the central nervous system neurotransmitters, drugs or conditions that excite increase cyclic guanosine 3',5'-monophosphate (cGMP), an effect mediated by the neuromodulator nitric oxide, whereas those that sedate decrease cGMP. Volatile anesthetics were shown to decrease cerebellar cGMP, an effect that correlates with their anesthetic and anticonvulsant effect. Because alpha-2 adrenoceptor agonists have anesthetic properties, the role of the nitric oxide-cGMP pathway in the action of the alpha-2 adrenoceptor agonists clonidine and dexmedetomidine was investigated.
  
  
  METHODS
  Groups of mice were given, intraperitoneally, one dose of either 30-600 micrograms/kg clonidine, or 3-300 micrograms/kg D-medetomidine (dexmedetomidine) or L-medetomidine. The alpha-2 adrenoceptor antagonists, 0.3-5 mg/kg yohimbine or 1 mg/kg atipamezole, 1 mg/kg of the alpha-1 antagonist prazosin, and 10-300 mg/kg of the nitric oxide synthase inhibitors, N omega-nitro-1-arginine methylester and N omega-nitro-1-arginine, were given 10-20 min before the agonist. The mice were killed by microwave radiation focused to the head. Cyclic GMP was measured by radioimmunoassay in deproteinized extracts from different brain areas.
  
  
  RESULTS
  Clonidine and dexmedetomidine, at sedative doses, dose-dependently decreased cerebellar cGMP (ED50: 100 and 50 micrograms/kg for clonidine and dexmedetomidine, respectively). This effect was inhibited by yohimbine and atipamezole, but not by prazosin, confirming the alpha-2 nature of the response to the agonists. L-medetomidine, which has no sedative/hypnotic effect, did not decrease cGMP. Pretreatment of the mice with a maximum dose of 100 mg/kg of a nitric oxide synthase antagonist abolished the cGMP response to the agonists. Similar results were obtained in the cerebral cortex, hippocampus and caudate nucleus.
  
  
  CONCLUSIONS
  The results suggest that the nitric oxide-cGMP pathway is an effector system coupled to the alpha-2 adrenoceptor mediating sedation.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Vulliemoz
authors.forename: H
authors.initials: H
authors.lastname: Shen
authors.forename: L
authors.initials: L
authors.lastname: Virag
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology*; D006152:Cyclic GMP / Q000032:analysis*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D020926:Medetomidine; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D006152:Cyclic GMP; D003000:Clonidine; D020926:Medetomidine; D019331:NG-Nitroarginine Methyl Ester