The adrenal gland plays a pivotal role in the stress response since this response involves the hypothalamic-pituitary-adrenal axis (HPAA) and the sympatho-adrenomedullary system (SAMS) as its two principal components. An important relation between the immune system and the other stress response systems is also centered on the adrenal gland. It is well known that the cortex secretes glucocorticoids while the medulla secretes epinephrine, two of the major effects of the stress response. Some other aspects, however, also deserve special consideration: The paracrine effects of the cortical secretion on the medullary cells through the special irrigation system of the gland and reciprocally the influence of the medulla upon the cortex, either by direct close contact or by local innervation. The influence of vascular events also needs to be considered as well as the existence of some local hormonal axis such as those resulting from the local production of renin or CRH in adrenal cells. Some other cells such as mast cells, macrophages and endothelial cells seem to play a role in the regulation of the adrenal cortex and hence in the tuning of the stress response. Stressors stimulate the release of CRH from the hypothalamic paraventricular nucleus inducing the secretion of ACTH from the pituitary and that of corticosteroids from the adrenal cortex. Through the activation of the sympathetic system the adrenal can be stimulated even before adequate levels of ACTH are reached. In conditions of chronic stress the adrenal cortex undergoes an adaptation that allows the hypersecretion of glucocorticoids to occur even without the increment of ACTH.

Despite great efforts devoted to clarifying the localization of proliferative activity in the adrenal cortex, the agents that stimulate proliferation remain controversial, and the nature of the stem cells from which cortical cells differentiate is incompletely understood. We studied proliferative activity in the rat adrenal cortex using an immunohistochemical method to detect the presence of the Proliferating Cell Nuclear Antigen (PCNA) (an intranuclear enzyme whose synthesis reaches the maximum intensity during the S-phase of the cell cycle). Groups of six rats were subjected to daily intraperitoneal injection of either corticotropin (ACTH1-24--0.2 mg/kg), dexamethasone (Dexa--4 mg/kg) or 0.9% saline for three consecutive days and killed 24 h after the last injection. Adrenal weight was significantly increased by ACTH treatment and reduced by Dexa. Concentrations of endogenous ACTH in plasma were lower in the Dexa group than in controls, and curiously, this was true in the ACTH1-24 treated group as well, probably in consequence of the increased corticosterone levels providing negative feedback at the hypothalamic-pituitary level. Corticosterone levels, as expected, were increased by the ACTH stimulus and reduced by the use of Dexa. Proliferating cell nuclear antigen immunostaining was close to zero in Dexa treated animals and low in controls. In ACTH treated rats, a significantly increased number of cells were positively stained. Positive cells were identified in both in zona glomerulosa (ZG) and zona intermedia (ZI) but many were located in the capsule. Zona fasciculata (ZF) and zona reticularis (ZR) were devoid of staining in all of these cases. We conclude that pharmacological doses of ACTH induce proliferation of capsular fibroblasts. Following descriptions by early 20th century researchers it is possible that these cells may also be stem cells and differentiate into adrenal cortex cells.

A morphological and autoradiographic study was made of the adrenal gland of adult male rats after autotransplantation. The simple technique involved placement of pieces of the adrenal gland in a dorsal plane between the skin and muscle. Animals for morphological studies were sacrificed at 2, 3, 4, 7, 15, 30, 90, and 180 days after autotransplantation. Those for autoradiographic studies were sacrificed at 2, 3, 7, and 15 days after autotransplantation, with 3H-thymidine being administered intraperitoneally 2 h before sacrifice. Sham-operated animals were used as controls. The majority of glandular adrenal cells suffered necrosis in the first days (2 and 3) after autotransplantation. Up until 15 days and after revascularization, morphological features of the cells were compatible with protein synthesis exhibiting a developed RER, scarce SER, and mitochondria with tubular and lamellar cristae. These data may correspond to a proliferative phase of glandular cells. At day 15, cells showed morphological signs of steroidogenic activity (mitochondria with vesicular cristae, increase of SER), and at day 30, an increased number of microvilli were seen. Between 30 and 90 days zonation of the adrenal was evident with glomerulosa, fasciculata, and reticular zones readily apparent. The quantitative analysis showed a significant increase of the volumetric density of mitochondria and microvilli between the days 7 and 30. Autoradiographic studies showed an intense labelling of fibroblast-like cells at days 2 and 3 and of glandular cells at days 7 and 15, which was confirmed by the quantitative studies. Corticosterone in autotransplanted animals decreased during the first 15 days, but after 30 days the values were similar to controls. The model reported here seems to be good for study of the regeneration of the adrenal gland and can be a simple, useful, and reproducible method for adrenal transplantation.

Activation of the stress system induces physiologic alterations as well as behavioural ones that ultimately improve the adaptability of the organism to adverse conditions. In our previous study on the morpho-functional evolution of the adrenal cortex, from birth to adulthood, the question of what could be the contribution of immobilization stress to the observed hormonal levels was brought up. Male adult rats were submitted to immobilization of variable duration. The antibody IZAb was used to allow a correct differentiation between the zona glomerulosa (ZG) and the inner zones of the cortex (IZ). A significant increase of the ACTH levels, especially at 5 and 30 min was observed. Corticosterone (B), surprisingly, revealed 2 peaks of secretion: one at 30 sec and another at 30 min. The area of the cortex, determined by an image analyser, only showed a slight decrease at 30 sec. The proportions of the cortical area occupied by ZG and IZ were unaltered. We concluded that a corticosterone peak at 30 sec precedes the elevation of ACTH induced by stress. Only the second peak, in view of its parallel course to ACTH, can be attributed to an effect of this pituitary hormone.

Adrenal gland autotransplantation, an interesting model of adrenal regeneration, provides the reconstruction of distinct functional and morphological zonae. An immunohistochemical study of the adrenal gland of adult male rats after autotransplantation and endothelin-1 (ET-1) stimulation was carried out. The technique involved total adrenalectomy and immediate autotransplantation of small adrenal pieces under the skin of the dorsal region. The animals were killed 90 days after the autotransplantation and 1 h after intravenous ET-1 administration. Sections of recovered adrenal grafts were incubated with IZAb, a monoclonal antibody which interacts with an antigen (IZAg) predominantly found in rat adrenal inner zones. Saline-treated control autotransplanted animals showed IZAb immunostaining in almost all adrenocortical tissue, with the exception of small clusters of cells beneath the capsule. ET-1-treated animals exhibited an extended zone devoid of immunostaining and located in the subcapsular area. In addition, ET-1-stimulated animals showed significant increases in aldosterone as well as corticosterone concentrations in plasma. These results revealed that ET-1 stimulated the development of an extended subcapsular zone lacking IZAg expression, an effect that suggests its role in zona glomerulosa induction in these animals.