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 (Cl) 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 (hGHRH(1-29)), 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 hGHRH(1-29), (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 mu g L-692,429 resulted in increased plasma GH levels within 5 min, which remained elevated for up to 15 min (Cl 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, T-4, and T-3 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 GPI 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. (C) 1908 Academic Press.