title: Selectivity of atipamezole, yohimbine and tolazoline for alpha-2 adrenergic receptor subtypes: implications for clinical reversal of alpha-2 adrenergic receptor mediated sedation in sheep.
abstract: The alpha2-adrenergic receptor antagonists, yohimbine, atipamezole and tolazoline, are used in veterinary medicine as reversal agents for the sedative/hypnotic effects of alpha2-agonists. Ruminants have increased sensitivity to the sedative/hypnotic effects of alpha2-agonists compared to other species. The receptors mediating the sedative effects of alpha2-agonists are located primarily on locus coeruleus neurons in the pons of the lower brainstem. Four pharmacological subtypes of the alpha2-adrenergic receptor (A,B, C and D) have been identified based on differences in ligand affinity. The aim of this study was to: 1) determine the pharmacological profile of atipamezole, yohimbine and tolazoline at the four alpha2-adrenergic receptor subtypes and; 2) determine whether these agents differ in their affinities at the alpha2-adrenergic receptor present in the sheep brainstem. In inhibition binding studies against the selective alpha2-adrenergic receptor ligand [3H]-MK-912, tolazoline showed the lowest affinity for all four alpha2-adrenergic receptor subtypes compared to yohimbine and atipamezole. The affinities of yohimbine and atipamezole were similar at the alpha2A-, alpha2B- and alpha2C-adrenergic receptors but differed by approximately 100 fold at the alpha2D-adrenergic receptor. Atipamezole had a 100 fold higher affinity at the alpha2D-adrenergic receptor when compared to yohimbine. To determine the ligand binding characteristics of these agents at the alpha2-adrenergic receptor in sheep brainstem, membranes were labelled with [3H]-MK-912 and inhibition competition curves were performed. Atipamezole showed approximately a 100 fold higher affinity for the sheep brainstem alpha2-adrenergic receptor compared to yohimbine which was similar to what was observed for the alpha2D-adrenergic receptor in PC12 cells transfected with RG-20. The results from these studies suggest that atipamezole has a high affinity for the alpha2D-adrenergic receptor that appears to be the receptor subtype in sheep brainstem.
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, Auburn University, College of Veterinary Medicine, Alabama 36849, USA. schwadd@vetmed.auburn.edu
authors.forename: D D
authors.initials: DD
authors.lastname: Schwartz
authors.forename: T P
authors.initials: TP
authors.lastname: Clark
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000502:physiology; D012756:Sheep; D014043:Tolazoline / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D015016:Yohimbine; D014043:Tolazoline