title: Mechanism of the lipid-mobilizing effect of alpha-2 adrenergic antagonists in the dog.
abstract: Alpha-2 adrenergic antagonists may constitute putative antiobesity agents. These drugs may act: 1) by blockade of the antilipolytic alpha-2 adrenoceptor on fat cell membranes and 2) by activation of the sympathetic adrenergic system (blockade of central and presynaptic alpha-2 adrenoceptors). Studies were undertaken in the dog, a species possessing fat cell alpha-2 and beta-adrenoceptors in order: 1) to define and compare the metabolic and endocrinological impacts of recently discovered alpha-2 antagonists [idazoxan and SK&F 86,466 (6-chloro-N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine)] and of an older one (yohimbine) and 2) to dissociate the contribution of the noradrenergic activation from a postsynaptic action on fat cell and endocrine pancreas alpha-2 adrenoceptors. Binding studies showed that the three compounds have similar affinities for the alpha-2 adrenoceptor on both cerebrocortical and fat cell membranes. Their ability to suppress the antilipolytic effect of an alpha-2 agonist [UK-14,304 (5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline)] on isolated fat cells was equivalent. Yohimbine perfusion induced a dose-dependent increase in plasma nonesterified fatty acids (NEFA) and immunoreactive insulin concentrations. At equivalent doses, the three alpha-2 adrenergic antagonists induced NEFA mobilization, increase in immunoreactive insulin and norepinephrine plasma levels with an order of potency: yohimbine much greater than idazoxan greater than or equal to SK&F 86,466. The weakest effect on sympathetic activation was with SK&F 86,466. The effects of yohimbine were suppressed completely by pretreatment with propranolol. Clonidine infusion reduced NEFA levels in dogs. Yohimbine but not SK&F 86,466 abolished completely this lowering effect of clonidine on NEFA and glycerol levels.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Laboratoire de Pharmacologie Médicale, Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale U-317, Université Paul Sabatier, Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Taouis
authors.forename: M
authors.initials: M
authors.lastname: Berlan
authors.forename: P
authors.initials: P
authors.lastname: Montastruc
authors.forename: M
authors.initials: M
authors.lastname: Lafontan
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001667:Binding, Competitive; D001786:Blood Glucose / Q000032:analysis; D002540:Cerebral Cortex / Q000378:metabolism; D004285:Dogs; D005230:Fatty Acids, Nonesterified / Q000097:blood; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D008053:Lipid Mobilization / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D011433:Propranolol; C039139:benalfocin