Influence of prolonged glucocorticoid treatment on intracellular mechanisms involved in ACTH secretion in the rat

• Published in: Journal of molecular endocrinology Vol. 1; no. 3; pp. 203 - 212
• Main Authors: Nicholson, S A, Gillham, B, Jones, M T
• Format: Journal Article
• Language: English
• Published: England BioScientifica 01.11.1988
• Subjects: Adrenocorticotropic Hormone - secretion; Animals; Arginine Vasopressin - physiology; Corticotropin-Releasing Hormone - physiology; Culture Techniques; Cyclic AMP - metabolism; Inositol Phosphates - metabolism; Male; Pituitary Gland, Anterior - drug effects; Pituitary Gland, Anterior - metabolism; Prednisolone - analogs & derivatives; Prednisolone - pharmacology; Rats; Rats, Inbred Strains; Second Messenger Systems - drug effects
• ISSN: 0952-5041; 1479-6813
• DOI: 10.1677/jme.0.0010203

ABSTRACT Two chemically characterized peptides, arginine vasopressin (AVP) and corticotrophin-releasing factor-41 (CRF-41), known to stimulate ACTH secretion by interaction with their respective specific receptors on the corticotroph, were shown to cause the accumulation of phosphate esters of inositol (IP) and adenosine 3′,5′-monophosphate (cAMP) respectively when added to rat anterior pituitary fragments incubated in vitro. The former 'second messenger' response (IP production) was unaffected in tissues removed from animals treated with prednisolone in the drinking water (1035 μmol/1) for 14 days. On the other hand, the cAMP response, whilst still present, was inhibited by some 50% in tissues taken from such animals. In contrast, pituitary glands from steroid-treated rats failed to respond to challenge with a variety of substances expected to cause the release of ACTH by mimicking or provoking the production of IP or cAMP. Indeed, of the wide range of ACTH secretagogues tested, only the phospholipase A2 activator melittin was able to cause attenuated ACTH release from tissues removed from treated rats. The failure to provoke ACTH release from tissues removed from steroid-treated animals was also seen when submaximal concentrations of CRF-41 or AVP, or hypothalamic extract or 48 mmol K+/1 were used as the stimuli. The staged recovery of the ACTH secretory response and IP and cAMP accumulation in vitro following the withdrawal of prednisolone treatment was also investigated. A cAMP response that did not differ significantly from that of control tissue and a normal ACTH response to K+ and to melittin were all recovered by 3 days after withdrawal, and the response to cholera toxin showed a partial recovery. Responses to all stimuli of ACTH secretion which cause their effect by entering the corticotrophs were normal by 5 days after withdrawal, when the response to CRF-41 was still significantly, and that to AVP still slightly, reduced compared with controls. Surprisingly, restoration of the ACTH response was most delayed when the expectedly most potent extracellular stimulus (hypothalamic extract) was used. In this case, release was still significantly impaired 7 days after steroid withdrawal. The results show that the glucocorticoid acts to compromise several distinct steps in the process whereby extracellular signals such as CRF-41 and AVP cause the secretion of ACTH. The only step that appears to be spared is the generation of IP by AVP. The staging of the recovery of the ACTH response following steroid withdrawal suggests that adenylate cyclase activation and release mechanisms recover first (by 3 days), then the coupling of individual second messenger production to ACTH synthesis and release (by day 5) and finally the integrated response to extracellular stimuli, which requires 7 or more days. From the present data, however, it is not clear why the recovery of the normal responses to intra- and extracellular signals stimulating ACTH secretion are temporally dissociated.