REGULATION OF PITUITARY CORTICOTROPIN-RELEASING HORMONE (CRH) RECEPTORS BY CRH - INTERACTION WITH VASOPRESSIN

The physiological regulation of ACTH secretion is largely dependent on the interactive effects of CRH and vasopressin (VP) in the pituitary corticotroph. The importance of the magnocellular and parvicellular hypothalamic systems as a source of VP for pituitary regulation was studied by analyzing the effects of endogenous activation of these systems or VP infusion on the ability of CRH to regulate its receptor sites in the anterior pituitary. CRH receptors were measured by binding of [I-125]Tyr-ovine CRH to membrane-rich fractions of anterior and neurointermediate pituitary lobes. Minipump infusion of 100 ng/min CRH for 48 h caused a 40% decrease in the anterior pituitary CRH receptor concentration. Simultaneous infusion of VP markedly potentiated the effect of CRH, but only at doses that elevated plasma VP to levels in the range of those in the pituitary portal circulation. Activation of the magnocellular vasopressinergic system by 60 h of water deprivation increased plasma VP levels from 0.5 +/- 0.1 to 11.8 +/- 0.6 pg/ml, but had no effect on the anterior pituitary CRH receptor concentration in control rats or animals receiving CRH infusion (100 ng/min for 48 h). The CRH receptor concentration was significantly increased in neurointermediate pituitary membranes from water-deprived rats. When the parvicellular vasopressinergic system was activated by 14 days of repeated restraint stress, there was a significant enhancement in the ability of CRH to decrease anterior pituitary CRH receptors (33% and 62% in control and stressed rats, respectively). The concomitant infusion of 200 ng/min of the VP antagonist [(mercapto cyclopentamethylene propionic acid)-[methyl-tyrosine]arginine VP] during the CRH infusion in chronically stressed rats, significantly reduced the magnitude of the pituitary CRH receptor loss from a 62% to a 43% decrease (P < 0.01). In conclusion, exogenous VP modulates pituitary CRH receptor regulation by CRH only at doses sufficiently high to provide peripheral VP concentrations in the range of the circulating levels in hypophysial-portal blood. Furthermore, the demonstration that chronic endogenous activation of the parvicellular, but not the magnocellular, vasopressinergic system enhances the down-regulatory effect of CRH on anterior pituitary CRH receptors is in support of a critical role of parvicellular VP in the control of the corticotroph function.