The Development and Study of the Glucocorticoid Receptor Blockade Animal Model / 第二军医大学学报

ABSTRACT

In order to study the physiological action of glucocorticoid receptor (GR) in intact animal, an animal model of GR depletion was developed in the rat by mifepristone (RU486), an antagonist of GR. Mifepristone 50 mg/kg body weight mixed in polyvinyl alcohol (PVA) was injected intramuscularly every 12 h in order to maintain the plasma mifepristone at the concentration of about 10-6mol/L for 72 h. In the meanwhile, the plasma corticosterone (B) was stabilized at about 15 ?g/dl by unilateral adrenalectomy 3 d before. In this model mifepristone occupied 88.1 ?10.7% of the total GR in hepatic, brain cytosol and thymocytes as measured by the exchange assay with [3H]dexamethasone (Dex) as ligand. Some indexes of glucocorticoid response were measured in the control, model and bilateral adrenalectomized (AdxT) rats. The polymorphonuclear eosinophil leukocyte (PME) count in blood and phospholipase A2(PLA2) activity in serum were decreased and tyrosine aminotransferase (TAT) activity of the liver was elevated in the control rats after stress provoked by epinephrine, but these changes were reversed in the model rats as well as in the AdxT rats. Thus it may be concluded that decrease of GR to about 12% may result in adrenoglucocorticoid insufficiency in spite of the normal functioning adrenal gland and high plasma level of B. So far as we know this is the first success to produce experimental endocrine insufficiency in a receptor depletion animal model and to quantitate the occupational threshold of about 12% of the total GR in rats.