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The acute effect of a new GH-releasing peptide, hexarelin (1 mg, iv), on GH secretion and the mechanisms involved in its changes were investigated in conscious sheep. Peripheral GH levels and GH-releasing hormone (GHRH) and somatostatin concentrations in hypophysial portal blood were measured in six rams. An increase in jugular GH levels was observed 15 min after hexarelin injection (9.1 +/- 1.8 vs. 3.9 +/- 0.8 ng/ml; P < 0.05). This was associated with a stimulation of GHRH release into hypophysial portal blood (145.4 +/- 19.9 vs. 59.2 +/- 10.8 pg/ml; P < 0.01) without a change in somatostatin secretion. Our data indicate that GH-releasing peptide-induced GH stimulation in the sheep involves an activation of GHRH neurons in addition to the previously demonstrated direct effect on the pituitary cells.

GH secretion is stimulated by the administration of an alpha 2-adrenergic agonist, clonidine, in several species, including man. This action is probably mediated at the level of the hypothalamus, where the drug may act through inhibition of somatostatin (SRIH) and/or stimulation of GH-releasing hormone (GHRH) release. We have investigated the mode and site of action of clonidine in sheep, because it is possible to collect hypophysial portal blood for the simultaneous determination of GHRH and SRIH in this species under conscious unstressed conditions. Clonidine injection (0.3 mg, iv) resulted in a significant, immediate, and short-lasting (30-min) increase in peripheral GH (14.4 +/- 3.1 vs. 4.8 +/- 1.1 ng/ml; P < 0.01) and portal GHRH (2.7 +/- 0.5 vs. 1.0 +/- 0.2 pg/min; P < 0.01) levels. No change in SRIH secretion was recorded during the same period. Next, we tested the effect of clonidine in sheep actively immunized against GHRH or SRIH. The alpha 2-adrenergic agonist did not affect GH secretion in the anti-GHRH group, whereas immunization against SRIH did not modify the GH response. Finally, we observed that clonidine did not influence GH release from cultured ovine pituitary cells. These data suggest that clonidine acts centrally to stimulate hypophysial GH secretion in the sheep and that this effect is mediated through changes in GHRH, but not SRIH, release into hypophysial portal blood.

GH secretion is stimulated by the administration of cholinesterase inhibitors (such as pyridostigmine and neostigmine) in several species, including man. On the basis of indirect experiments, it has been postulated that this action is mediated by a decrease in hypothalamic somatostatin release. We have investigated the effect of neostigmine in sheep, since it is possible to collect hypophysial portal blood for GH-releasing hormone (GHRH) and somatostatin determination in this species under a conscious unstressed state. First, after i.v. injection of neostigmine (1 mg), a significant increase in plasma GH levels and an unequivocal potentiation of the GH response to GHRH were observed. Then, we observed that i.v. injection of neostigmine (1 mg) induced an immediate, short-lasting (30 min), and marked increase in GHRH (126.1 +/- 17 vs. 14.5 +/- 2.1 pg/ml; P < 0.01) levels in hypophysial portal blood of rams chronically implanted with perihypophysial cannulae. No change in somatostatin secretion was recorded during the same period. These data suggest that the stimulating effect of cholinergic drugs on GH secretion is mediated by stimulation of GHRH release. A direct effect of neostigmine at the level of pituitary gland is possible and may explain the potentiation of GHRH-induced GH release.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) and to an acute injection of CRF were determined in intact as well as in actively antiarginine vasopressin (AVP)-immunized rams. All immunized sheep developed antibodies to AVP, displayed diabetes insipidus, and looked healthy in spite of their lower gain weight. Basal secretion and diurnal variations of ACTH and cortisol were unaltered in the group of anti-AVP-immunized animals. In contrast, ACTH and cortisol responses to both types of stress and CRF injection were significantly reduced compared to those in controls. These results suggest that endogenous AVP plays a physiological role in the corticotropic response to stress. However, endogenous AVP does not appear to affect basal secretion and diurnal variations of ACTH and cortisol.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) or to an acute injection of lysine-vasopressin were studied in intact and anti-corticotropin-releasing factor (CRF) actively immunized rams. Immunization was obtained by the injection of synthetic ovine CRF coupled to BSA with carbodiimide. All animals developed antibodies anti-CRF and displayed an alteration of their general condition and a body weight reduction. The mean basal ACTH and cortisol secretion as well as the number and mean amplitude of diurnal pulses of these hormones was significantly reduced in the group of anti-CRF immunized rams. However, the reduction in all three parameters was much more pronounced for cortisol than for ACTH. No ACTH and cortisol response to insulin-induced hypoglycemia and isolation-restraint stress was observed. The stimulating action of lysine-vasopressin on ACTH release was significantly reduced as compared to controls. These results indicate that CRF is a major physiological component of the ovine hypothalamo-hypophysial-adrenal axis and participates in the events that regulate ACTH and cortisol diurnal variations and response to stress.