Pituitary and extrapituitary action sites of the novel nonpeptidyl growth hormone (GH) secretagogue L-692,429 in the chicken.
Chickens were used as a model to further analyze the efficacy and specificity of L-692,429, a novel nonpeptidyl mimic of growth hormone (GH)-releasing peptide-6 (GHRP-6), which is a specific GH-releasing secretagogue in mammals. Actions at the level of the pituitary and the hypothalamus were studied. Pituitaries isolated from 1-day-old (C1) chicks responded in a dose-dependent manner to L-692,429 (ED50 = 10 nM). Using equimolar concentrations of thyrotropin-releasing hormone (TRH), human GH-releasing hormone (hGHRH1-29), and L-692,429 (10 nM), L-692,429 had 20-25% the in vitro potency of the two endogenous releasing factors. There was an additive effect between hGHRH1-29 (10 nM) and L-692,429 (10 or 100 nM) on GH release from C1 pituitaries but no such additive effect was observed when pituitaries were exposed to both TRH (10 nM) and L-692,429 (100 nM). An acute challenge with 50 microg L-692,429 resulted in increased plasma GH levels within 5 min, which remained elevated for up to 15 min (C1 chickens). This increase in GH was accompanied by a drop in hypothalamic TRH content by 5 min. Hypothalamic somatostatin (SRIH) content did not change. Plasma corticosterone concentrations were increased following L-692,429 treatment, whereas plasma alpha-subunit, T4, and T3 levels were unchanged. To confirm the role of the decreased hypothalamic TRH concentrations in the GH-releasing activity of L-692,429 in the chicken, chickens (C1) were pretreated with normal rabbit serum (NRS) or a TRH antiserum (1/50) 1 h prior to the L-692,429 challenge. Both groups showed an increase in circulating GH but the increase was within 5 min inhibited by the TRH antiserum pretreatment, whereas no differences were noted in plasma corticosterone levels. It is concluded that in the chicken the GH secretagogue L-692,429 has a dual action site: (1) directly at the level of the pituitary and (2) centrally through an increase in hypothalamic TRH release.
Geris
K L
KL
Laboratory of Comparative Endocrinology, Naamsestraat 61, Leuven, B-3000, Belgium. kris.geris@bio.kuleuven.ac.be
Hickey
G J
GJ
Berghman
L R
LR
Visser
T J
TJ
Kühn
E R
ER
Darras
V M
VM
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002645:Chickens / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D013004:Somatostatin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology
D001552:Benzazepines; D010446:Peptide Fragments; D013777:Tetrazoles; C081455:L 692429; D013004:Somatostatin; D013973:Thyrotropin-Releasing Hormone; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C059148:somatotropin releasing hormone (1-29); D003345:Corticosterone