Endothelin-1 enhances thymocyte proliferation in monolaterally adrenalectomized rats with contralateral adrenocortical regeneration.

Endothelins (ETs) are a family of vasoactive peptides widely distributed in the body systems, where they exert pleiotropic biological effects, acting through two main subtypes of receptors, named ETA and ETB. Evidence indicates that ET-1 plays a permissive role in the development of neural crest-derived structures, among which are the epithelial cells of the thymus. These cells are known to control proliferation and differentiation of thymocytes, a process requiring adequate levels of glucocorticoids. Therefore, we have investigated the effects of ET-1, that binds both ETA and ETB receptors, on thymocyte proliferation in monolaterally adrenalectomized rats with contralateral enucleated adrenal at day 4 and 8 of regeneration, when glucocorticoid production is very low and, respectively, rather normal. Metaphase index (percentage of metaphase arrested cells) of thymocytes is the lowest at day 4 of regeneration, and markedly rose at day 8, thereby confirming the need of sizable levels of circulating glucocorticoid for the maintenance of a normal rate of thymocyte proliferation. ET-1 markedly increased the mitotic index of thymocytes at both times of adrenal regeneration. At day 8 of regeneration, the ETA-receptor antagonist BQ-123 markedly lowered mitotic index of thymocytes, and annulled its ET-1-evoked raise. Conversely, the ETB-receptor antagonist BQ-788 was ineffective. Collectively, these findings clearly indicate that endogenous ETs, through the activation of ETA receptors, are involved in the maintenance and stimulation of thymocyte proliferation in the adult rat, thereby playing a possibly important role in the modulation of the immune-system functions.

Endothelin-1, acting via the A receptor subtype, stimulates thymocyte proliferation in the rat.

Endothelins (ETs) are a family of vasoactive peptides widely distributed in the body systems, where they carry out major autocrine/paracrine regulatory functions, acting through two main subtypes of receptors (ETA and ETB). Evidence suggests that ETs play a permissive role in the development of neural crest-derived craniofacial structures, among which the thymus. Therefore, we have investigated whether ETs regulate thymocyte proliferation in the adult rat ET-1 (which binds both ETA and ETB receptors) increased the mitotic index (% of metaphase-arrested cells) in the thymus cortex, while ET-3 (which preferentially binds ETB) and the selective ETB-receptor agonists BQ-3020 and IRL-1620 did not. The ETA-receptor antagonists BQ-123 and BQ-610, but not the ETB-receptor antagonist BQ-788, abolished the ET-1 effect. Moreover, BQ-123 and BQ-610, when administered alone, evoked a significant decrease in the mitotic index. Collectively, these findings clearly indicate that endogenous ETs, through the activation of ETA receptors, are involved in the maintenance and stimulation thymocyte proliferation in the adult rat, thereby playing a possible important role in the modulation of the immune-system functions.

Effect of 5-bromo-2'-deoxyuridine on the proliferative activity of thymus and regenerating adrenal cortex.

5-Bromo-2'-deoxyuridine (BrdU) has been recently found to enhance adrenal glucocorticoid secretion in rats. Since BrdU-labeling is today the most employed technique for assessing cell proliferation, we have investigated whether this side-effect of BrdU may influence mitotic activity (as evaluated by metaphase-arrested cell counting) in the thymus cortex and regenerating adrenal cortex. BrdU (1 mg/100 g body weight) evoked a 6-fold rise in the blood level of corticosterone in intact rats, but not in animals bearing regenerating adrenals, in which glucocorticoid secretion was very low. Mitotic index in the thymus of intact rats was not changed by BrdU, but it was strongly depressed in regenerating adrenals. These findings rule out the possibility that the glucocorticoid secretagogue action of BrdU exerts a sizable effect on the proliferative activity of both thymus and adrenal cortex. The marked lowering in the mitotic rate in the regenerating adrenal cortices could be ascribed to the well-know differentiation promoting action of BrdU, a finding which, if confirmed, would make highly unreliable the use of BrdU-labeling technique in cultures of adrenocortical cells.