Alpha 2-antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect of oral yohimbine in healthy male volunteers.
Investigations were carried out to analyse the interactions of alpha 2-antagonists (yohimbine, idazoxan, SK & 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 greater than idazoxan greater than SK & 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Galitzky
J
J
Laboratoire de Pharmacologie Clinique et Médicale, Université Paul Sabatier, Toulouse, France.
Taouis
M
M
Berlan
M
M
Rivière
D
D
Garrigues
M
M
Lafontan
M
M
D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D001552:Benzazepines / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D015444:Exercise; D006801:Humans; D019329:Idazoxan; D008053:Lipid Mobilization / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D015016:Yohimbine / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D004146:Dioxanes; D015016:Yohimbine; D019329:Idazoxan; C039139:benalfocin; D004837:Epinephrine