title: 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.
authors.affiliation: Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Hickey
authors.forename: J
authors.initials: J
authors.lastname: Drisko
authors.forename: T
authors.initials: T
authors.lastname: Faidley
authors.forename: C
authors.initials: C
authors.lastname: Chang
authors.forename: L L
authors.initials: LL
authors.lastname: Anderson
authors.forename: S
authors.initials: S
authors.lastname: Nicolich
authors.forename: L
authors.initials: L
authors.lastname: McGuire
authors.forename: E
authors.initials: E
authors.lastname: Rickes
authors.forename: D
authors.initials: D
authors.lastname: Krupa
authors.forename: W
authors.initials: W
authors.lastname: Feeney
authors.forename: B
authors.initials: B
authors.lastname: Friscino
authors.forename: P
authors.initials: P
authors.lastname: Cunningham
authors.forename: E
authors.initials: E
authors.lastname: Frazier
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Laroque
authors.forename: R G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology*; D002490:Central Nervous System / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D006854:Hydrocortisone / Q000097:blood; D007031:Hypothalamus / Q000601:surgery*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009919:Orchiectomy; D013552:Swine; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001552:Benzazepines; C091588:L 692585; D013777:Tetrazoles; D007986:Luteinizing Hormone; D013006:Growth Hormone; D003346:Corticotropin-Releasing Hormone; D013007:Growth Hormone-Releasing Hormone; D006854:Hydrocortisone