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Clonidine is an α2-adrenergic agonist, historically known to treat high blood pressure. Further studies showed that it could be used in the treatment of neuropsychiatric disorders. Afterwards, it has been reported that clonidine stimulated growth hormone (GH) release in many species including man. Using a transnasal surgery technique in awake sheep that allowed accessing hypothalamopituitary portal vessels, our laboratory previously reported that the injection of clonidine in sheep induced a significant, immediate and short-lasting increase in peripheral GH and portal GH-releasing hormone (GHRH) levels. In this study, we show that the clonidine-induced peripheral GH and portal GHRH increase in sheep appears to be mediated by the tachykinin NK2 receptor.

Changes in corticotropin (ACTH) and glucocorticoid secretion have been described during disturbances of body fluid homeostasis and attributed to alterations in arginine vasopressin (AVP) secretion from magnocellular hypothalamic neurons. In order to further characterize the mechanisms involved in the interactions between body fluid alterations and pituitary adrenal function, we manipulated osmolality and volemia in sheep under stimulation of the pituitary-adrenal axis by acute injection of endotoxin. We have recently shown that endotoxin injection induces a long-lasting release of both corticotropin releasing hormone (CRH) and AVP into hypophysial portal blood, and an early stimulation of AVP secretion into peripheral vessels, thus suggesting a joint activation of magnocellular and parvocellular neurons of the PVN. We used the same experimental model to investigate the effect of combined volume loading and plasma dilution (achieved by 1-deamino-8-D-arginine (dDAVP) administration together with infusion of 2 liters of 2.5% glucose solution) on CRH, AVP, ACTH and cortisol responses to endotoxin stimulation. In volume-loaded animals, ACTH and cortisol responses to endotoxin were significantly blunted and we observed a parallel decrease in portal CRH and jugular and portal AVP levels. These data show that hypoosmolality and/or hypervolemia reduce(s) ACTH and cortisol response to stress in sheep as in other species. They strongly suggest that this reduction in ACTH and cortisol responses to endotoxin involve not only magnocellular hypothalamic neurons secreting AVP, as usually assumed, but also PVN parvocellular neurons secreting both CRH and AVP.

During the postnatal period from day 2 to day 10 of life, basal and stress-induced adrenocorticotropic hormone (ACTH) and corticosterone releases are low as compared with adults. This period has been called the ‘stress-hyporesponsive period’, and its mechanisms are yet undetermined. In this study, we have tested the effects of substances excitatory to neuronal activity on the hypothalamic-pituitary-adrenal (HPA) axis. In 7-day-old rats, administration of the excitatory amino acid (EAA) agonists N-methyl-D-aspartic acid (NMA), quisqualic acid, and kainic acid (KA) induced a large increase in plasma ACTH and corticosterone concentrations. All three EAA induced a rapid and potent stimulation of ACTH release within 30 min, the effect on corticosterone secretion being weaker. KA was the more potent EAA, followed by NMA and quisqualic acid. The effect of NMA on the HPA axis was inhibited by pretreatment with a competitive antagonist to N-methyl-D-aspar-tic acid receptors, D, L-2-amino-5-phosphonovaleric acid. We next sought to determine which level of the HPA axis was affected by EAA administration. Several EAA (glutamic acid, N-methyl-D-aspartic acid, and KA from 10-5 to 10-2M) had no stimulating action on ACTH release from 7-day-old anterior pituitary glands incubated in vitro. In vivo, the stimulating effect of NMA and KA on in vivo ACTH release was blocked after passive immunization with an anti-corticotropin-releasing hormone antiserum, but not after injection of an anti-arginine vasopressin antiserum. These results suggest that during stress-hyporesponsive period, the HPA axis can be stimulated by excitatory substances acting at the hypothalamic or suprahypothalamic level.

Plasma adrenocorticotropic hormone (ACTH) and corticosterone were detectable in fetal plasma on day 16 of pregnancy. Thereafter, the levels of both hormones increased steadily in a parallel manner and reached a peak on day 19 of pregnancy. Administration of an antiserum anti-rat corticotropin-releasing factor (CRF) to pregnant rats was followed by a significant decrease in fetal plasma corticosterone as early as day 17. Plasma ACTH measured under the same experimental conditions on day 19 of gestation was also significantly decreased. Similar results have been obtained with fetal plasma collected from adrenalectomized pregnant rats, indicating that the plasma corticosterone decrease in fetuses after immunoneutralization of CRF reflects changes in fetal adrenal secretion and not a diminution of corticosterone transfer from the maternal to the fetal circulation. These results show that endogenous CRF begins to play a physiological role in the regulation of ACTH and corticosterone secretion as early as in 17-day-old fetuses. This effect may occur before the connections between the neurosecretory CRF axons and the hypophysial portal capillaries have been established. Therefore, endogenous CRF may enter the hypophysial portal circulation after intercellular diffusion in hypothalamic tissue.

The concentration of corticotropin-releasing factor (CRF)-binding sites decreases in the rat anterior pituitary after adrenalectomy; this change may be related either to a direct effect of the circulating glucocorticoids at the pituitary level or to a desensitization of CRF receptors through an increased CRF release in hypophysial portal blood. In order to examine the latter possibility we have measured plasma adrenocorticotropin hormone (ACTH) levels and the number of anterior pituitary CRF binding sites in sham-operated and 24-hour adrenalectomized rats after blockade of endogenous CRF by passive immunization with an antiserum anti-rat CRF (CRF-AS), or after injection of normal rabbit serum (NRS). In NRS-injected rats, after sham operation, plasma ACTH concentration increased (227 + 34 vs. 118 ± 19 pg/ml in controls) without change in CRF-binding sites capacity (20.7 ± 2.6 vs. 24.6 ± 3.5 fmol/mg protein in controls). Adrenalectomy induced a large rise in plasma ACTH (785 ± 89 pg/ml) and a decrease in the number of CRF-binding sites (12.2 ± 1.7 fmol/mg protein). After CRF-AS injection, plasma ACTH was normalized in sham-operated animals (149 ± 24 pg/ml) and significantly reduced in adrenalectomized rats (472 ± 76 pg/ml); the adrenalectomy-induced decrease in the number of CRF-binding sites was unaffected by the CRF-AS administration (12.2 ± 1.7 fmol/mg protein). The administration of dexamethasone to adrenalectomized rats significantly reduced plasma ACTH concentrations (23.3 ± 10.6 pg/ml) and prevented the loss in CRF-binding sites capacity (20.7 + 1.3 fmol/mg protein). Affinity of CRF for its binding sites was unchanged in all the groups studied. These findings suggest that the postadrenalectomy reduction in the number of anterior pituitary CRF-binding sites may be mainly due to a direct glucocorticoid effect at the pituitary level rather than a consequence of a possible increased CRF secretion.