Human fat cell alpha-2 adrenoceptors. I. Functional exploration and pharmacological definition with selected alpha-2 agonists and antagonists.
This study was undertaken to investigate more fully the pharmacological characteristics of the human fat cell alpha-2 adrenoceptor. Biological assays were performed on intact isolated fat cells while radioligand binding studies were carried out with [3H]yohimbine in membranes. These pharmacological studies brought: 1) a critical definition of the limits of the experimental conditions required for the exploration of alpha-2 adrenergic responsiveness on human fat cells and membranes; 2) an improvement in the pharmacological definition of the human fat cell postsynaptic alpha-2 adrenoceptor. Among alpha-2 agonists, UK-14,304 was the most potent and the relative order of potency was: UK-14,304 greater than p-aminoclonidine greater than clonidine = B-HT 920 greater than rilmenidine. For alpha-2 antagonists, the potency order was: yohimbine greater than idazoxan greater than SK&F-86,466 much greater than benextramine; 3) a description of the impact of benextramine (irreversible alpha-1/alpha-2 antagonist) on human fat cell alpha-2 adrenergic receptors and on human fat cell function; the drug inactivates the alpha-2 adrenergic receptors with a minor impact on beta adrenergic receptors and without noticeable alterations of fat cell function as assessed by preservation of beta adrenergic and Al-adenosine receptor-mediated lipolytic responses; and 4) a definition of the relationship existing between alpha-2 adrenergic receptor occupancy, inhibition of adenylate cyclase activity and antilipolysis with full and partial agonists. The existence of a receptor reserve must be taken into account when evaluating alpha-2 adrenergic receptor distribution and regulation of human fat cells.
Galitzky
J
J
Institut National de la Santé et de la Recherche Médicale (I.N.S.E.R.M., U.317), Université Paul Sabatier, Toulouse, France.
Mauriege
P
P
Berlan
M
M
Lafontan
M
M
D000243:Adenosine Deaminase / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D000068438:Brimonidine Tartrate; D003538:Cystamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006801:Humans; D008066:Lipolysis / Q000187:drug effects; D008875:Middle Aged; D011810:Quinoxalines / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000032:analysis; D015016:Yohimbine / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D000068438:Brimonidine Tartrate; C029998:benextramine; D006160:Guanosine Triphosphate; D000243:Adenosine Deaminase; D003538:Cystamine