ACTIVATION OF THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS BY THE GROWTH-HORMONE (GH) SECRETAGOGUE, GH-RELEASING PEPTIDE-6, IN RATS

GH-releasing hexapeptide (GHRP-6) is a synthetic secretagogue that sti mulates the release of GH by acting at both hypothalamic and pituitary sites. GHRPs also consistently elicit small, but significant, increas es in plasma concentrations of ACTH and adrenal steroids. As these sec retagogues do not release ACTH directly, they probably interact with t he hypothalamic peptidergic systems controlling ACTH release, such as CRH and arginine vasopressin (AVP). We have now examined the activatio n of the hypothalamo-pituitary-adrenal axis by GHRP-6 in conscious rat s. In a series of experiments, rats were injected iv with 10 mu g GHRP -6, 2 mu g CRH, 0.5 mu g AVP, or saline, alone or in combination, and serial plasma samples withdrawn and assayed for ACTH, corticosterone, and GH. CRH and AVP increased plasma ACTH levels in all rats, whereas ACTH and corticosterone responses to GHRP-6 were variable and were dep endent on the prevailing activity of the hypothalamo-pituitary-adrenal axis. GHRP-6 stimulated the largest ACTH responses in rats that had t he lowest basal plasma ACTH and corticosterone levels before GHRP-6 ad ministration. GHRP-6 given in combination with CRH did not increase AC TH levels beyond the response to CRH alone (change in ACTH, 1570 +/- 2 07 us. 1714 +/- 245 pg/ml), whereas the combination of GHRP-6 and AVP markedly increased ACTH levels compared with the effects of AVP alone (change in ACTH, 5587 +/- 669 us. 2338 +/- 451 pg/ml; P < 0.05). The G H responses to GHRP-6 were significantly greater in rats with low basa l plasma ACTH and corticosterone levels than in rats with elevated ACT H and corticosterone levels (change in GH response, 119 +/- 27 vs. 29 +/- 7 ng/ml;P < 0.01). CRH alone significantly inhibited GH release (p re- us. 40 min post-CRH, 11.9 +/- 3.8 vs. 1.7 +/- 0.4 ng/ml; P < 0.05) , whereas AVP alone had no effect on GH levels. Neither CRH nor AVP ha d any effect on the GH response to GHRP-6. We suggest that GHRP-6 acts via the hypothalamus to mediate the release of ACTH, and that these e ffects are probably mediated at least in part via the release of endog enous CRH and are subject to regulation by circulating glucocorticoids .