MEDIATION BY THE CENTRAL-NERVOUS-SYSTEM IS CRITICAL TO THE IN-VIVO ACTIVITY OF THE GH SECRETAGOGUE L-692,585

To investigate the effect of hypophyseal transection (HST) on GH secre tagogue 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-operate d control group (SOC; n = 3). Treatments administered were L-692,585 ( 100 mu g/kg), human GH-releasing factor(1-29)NH, (GRF; 20 mu g/kg) or L-692,585 (100 mu g/kg) + GRF (20 mu g/kg) on days - 7 to - 3 before s urgery and days + 3 to + 8 after surgery. To evaluate the integrity of the pituitary gland, the animals were challenged with corticotropin-r eleasing hormone (CRH; 150 mu g) or GnRH (150 ng/kg) both before and a fter surgery. Blood was collected from - 60 to + 180 min post treatmen t 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 v s 25 +/- 3) resulting in a significant difference between groups. Foll owing surgery, significant differences were present in peak GH respons e (ng/ml) between SOC and HST groups following L-692,585 (79 +/- 6 vs 13.8 +/- 1.0); however, the response to L-692,55 + GRF was similar (11 5 +/- 8 vs 94 +/- 7). All animals responded to GRF; however, a signifi cant 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 differe nce was present after surgery (44.4 +/- 6.4 vs 14.6 +/- 2.1). No signi ficant difference was noted between the HST and SOC groups in response to CRH or GnRH either before or after surgery. These results indicate d 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 th e hypophyseal stalk dramatically decreased but did not ablate the GH o r cortisol response to L-692,585. Go-administration of L-692,585 + GRF induced an immediate GH response of similar magnitude in the intact a nd HST animal. We conclude that L-692,585 has a direct but limited act ion 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 wi th GRF at the level of the pituitary to induce a maximal GH response. These findings suggest that L-692,585 stimulates GH secretion by actin g in combination with GRF and interrupting the inhibitory tone of soma tostatin on the somatotroph.