α2‐Antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect of oral yohimbine in healthy male volunteers

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Abstract
Investigations were carried out to analyze the interactions of .alpha.2-antagonists (yohimbine, idazoxan, SK and F-86,466) with human fat cell .alpha.2-adrenoceptors. All the .alpha.2-antagonists enhanced the lipolytic potencies of epinephrine with an order of potency: yohimbine > idazoxan > SK and F-86,466; the same order was also found in 3H-yohimbine competition studies on human fat cell membranes. The most potent agent, yohimbine, was administered orally in humans to define the conditions of appearance and the time-course of a putative lipid-mobilizing action. Oral yohimbine administration (0.2 mg kg-1) elevated plasma glycerol and non-esterified fatty acids in fasting healthy subjects without significant action on heart rate or blood pressure during the time-course of the experiment. The lipid-mobilizing action of yohimbine was reinforced during physical exercise, completely suppressed after a meal and partially blocked by administration of propranolol (0.5 mg kg-1; 60 min before yohimbine). Plasma norepinephrine concentrations were increased (40-50%) after oral yohimbine administration. The rise in plasma catecholamine concentration elicited by yohimbine was not modified by propranolol treatment. The lipid-mobilizing effect of yohimbine could be attributable to: (i) the increase in synaptic norepinephrine with a resultant increment in lipolysis by .beta.-adrenergic agonism; (ii) a decrease in .alpha.2-adrenoceptor stimulation of human fat cell .alpha.2-adrenoceptors; (iii) a blockade of presynaptic .alpha.2-adrenoceptors. The use of highly selective .alpha.2-antagonists will allow investigations into .alpha.2-adrenoceptors, which may represent a novel locus for pharmacological intervention in lipid-mobilization strategies. It is questioned whether .alpha.2-antagonists would be useful in treatment or catecholamine-refractoriness and obesity.