Mechanism of the lipid-mobilizing effect of alpha-2 adrenergic antagonists in the dog.

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)