Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585

Abstract

To investigate the effect of hypophyseal transection (HST) on GH secretagogue activity of the non-peptidyl GH secretagogue L-692,585 in the conscious pig, male castrated swine were randomly assigned to either a hypophyseal stalk transection group (HST; n = 3) or to a sham-operated control group (SOC; n = 3). Treatments administered were L-692,585 (100 micrograms/kg), human GH-releasing factor(1-29)NH2 (GRF; 20 micrograms/kg) or L-692,585 (100 micrograms/kg) + GRF (20 micrograms/kg) on days -7 to -3 before surgery and days +3 to +8 after surgery. To evaluate the integrity of the pituitary gland, the animals were challenged with corticotropin-releasing hormone (CRH; 150 micrograms) or GnRH (150 ng/kg) both before and after surgery. Blood was collected from -60 to +180 min post treatment and assayed for GH, cortisol and LH. Before surgery, no significant difference (P > 0.05) in peak GH response (ng/ml) was present between the two groups (SOC vs HST) in response to L-692,585 (101 +/- 12 vs 71 +/- 9) or L-692,585 + GRF (171 +/- 21 vs 174 +/- 21). Only two out of three SOC vs three out of three HST pigs responded to GRF (13 +/- 2 vs 25 +/- 3) resulting in a significant difference between groups. Following surgery, significant differences were present in peak GH response (ng/ml) between SOC and HST groups following L-692,585 (79 +/- 6 vs 13.8 +/- 1.0); however, the response to L-692,585 + GRF was similar (115 +/- 8 vs 94 +/- 7). All animals responded to GRF; however, a significant difference was present between groups due to the magnitude of the responses. Whereas the cortisol responses (ng/ml) to L-692,585 in the SOC and HST groups were similar before surgery, a significant difference was present after surgery (44.4 +/- 6.4 vs 14.6 +/- 2.1). No significant difference was noted between the HST and SOC groups in response to CRH or GnRH either before or after surgery. These results indicated that L-692,585 induced an immediate GH response in the intact animal in contrast to GRF where the GH release was variable. L-692,585 also stimulated an immediate increase in cortisol levels. Transection of the hypophyseal stalk dramatically decreased but did not ablate the GH or cortisol response to L-692,585. Co-administration of L-692,585 + GRF induced an immediate GH response of similar magnitude in the intact and HST animal. We conclude that L-692,585 has a direct but limited action at the level of the pituitary and that an intact hypophyseal stalk is required for a maximal GH and cortisol response. L-692,585 acts with GRF at the level of the pituitary to induce a maximal GH response. These findings suggest that L-692,585 stimulates GH secretion by acting in combination with GRF and interrupting the inhibitory tone of somatostatin on the somatotroph.

Pharmacological characterisation of a new oral GH secretagogue, NN703

“…administration and compare it with hexarelin and MK677, which has previously been described to release cortisol in humans (33,34). The cortisol release is most likely mediated by ACTH release (15), which is in agreement with earlier findings in swine, where the effect on cortisol is abolished after disconnection of the hypothalamic stalk (26).…”

“…T max is about 10 min, which is also in agreement with other GHSs in different species, including man (26)(27)(28)(29).…”

Ghrelin in obesity and endocrine diseases

“…Systemic administration of ghrelin, or the synthetic hexarelin, has been shown to increase ACTH and cortisol levels in healthy subjects (Arvat et al, 2001;Korbonits et al, 1999a). A hypothalamic site of action of ghrelin on the hypothalamic-pituitaryadrenal (HPA) axis has been proposed, as transection of the hypophyseal stalk dramatically decreased cortisol responses to synthetic growth hormone secretagogue (GHS) treatment (Hickey et al, 1996). Furthermore these compounds fail to increase ACTH release from pituitary tissue in vitro (Shimon et al, 1998).…”

Estados de pseudo-Cushing

“…Teste da hexarelina A hexarelina é um peptídeo que estimula a secreção de ACTH hipofisário de uma maneira diferente da desmopressina (97). Acredita-se que a hexarelina age diretamente no hipotálamo, aumentando o ACTH via CRH endógeno ou outros fatores liberadores de ACTH hipotolâmicos.…”

“…Evidências mostram que após a desconexão hipotálamo-hipofisária, o efeito da hexarelina é completamente abolido (97,98) e que ainda essa droga é capaz de estimular a secreção de ACTH in vitro (99,100).…”