Failure to detect excessive stress-induced adrenal corticosterone secretion following amino-glutethimide withdrawal in the rat.

Abstract

Rats were fed a 0.8% aminoglutethimide diet for 2 weeks. Plasma corticosterone concentration was measured 20 min after an ether stress before and on various days during and after amino-glutethimide feeding. There was a significant depression of the corticosterone concentration within two days after starting the experimental diet which persisted throughout the period of drug administration. Within 1-2 days after drug withdrawal, plasma corticosterone response to ether had returned to control levels. There was no supranormal response up to 8 days after drug withdrawal, indicating that a marked increase in available cholesterol in the adrenal does not per se lead to an increase in hormone secretion. (Endocrinology 91: 600, 1972) MINO-GLUTETHIMIDE, a drug chemiL cally related to Amphenone, has been shown Received March 3, 1972. Supported by Grants from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health. to inhibit the synthesis of adrenal hormones. It apparently depresses the conversion of cholesterol to pregnenolone in the gland (1). This results in an accumulation of cholesterol in the adrenal and an enlargement of that organ, both reactions being dependent on an increased secretion of ACTH due to reduced negative feedback on the hypothalamic-pituitary complex conseNOTES AND COMMENTS 601 quent to the reduction of adrenal hormone secretion (2,3). The normal adrenal gland does not store large quantities of either the hormones it secretes or the precursors of these hormones. It was therefore of interest to determine if rats with large adrenal glands filled with cholesterol following amino-glutethimide treatment would exceed their normal capacity to secrete corticosterone in response to a standardized stress after the inhibitory effects of the drug had worn off but before adrenal cholesterol concentration had returned to normal. The large quantity of stored cholesterol might facilitate a supranormal synthesis and secretion of hormone. Materials and Methods Male Sprague-Dawley rats weighing approximately 250 g were used. They were housed 2-3 animals per cage in a room with controlled temperature (24 ± 1 C) and lighting (12 hr light: 12 hr dark, light cycle beginning at 6 AM). TWO experiments were performed. In each, one group received a diet of powdered Purina Lab chow containing 8 g of aminoglutethimide/kg. The control group received unadulterated Purina Lab chow. Both groups were given food and water ad lib. In the first experiment, the experimental group was fed amino-glutethimide for 14 days followed by Purina only for 8 days. In the second experiment, the amino-glutethimide diet was fed for 13 days, followed by Purina only for 4 days. As a standard stress, the rats were placed in a jar containing ether-saturated air for 2 min between 9 and 10 AM on various days. The animals were then returned to their home cage. Twenty min later, a 0.5-ml blood sample was obtained from the jugular vein under ether anesthesia. The sampling procedures were interdigitated between the amino-glutethimide and control groups to minimize skewing the data. Plasma corticosterone concentration was determined with a micro-modification of the fiuorometric method (4) in routine use in our laboratory. Upon completion of the second experiment, the adrenal glands were removed, trimmed, weighed on a torsion balance and the total cholesterol content determined by a modification of the ferric chloride reaction (5). Statistical significance of the data was analyzed with Student's Mest.