EFFECTS OF DEXAMETHASONE AND ALPRAZOLAM, A BENZODIAZEPINE, ON THE STIMULATORY EFFECT OF HEXARELIN, A SYNTHETIC GHRP, ON ACTH, CORTISOL AND GH SECRETION IN HUMANS

Hexarelin (HEX) is a synthetic GHRP which acts on specific receptors a t both the pituitary and the hypothalamic level to stimulate GH releas e both in animals and in humans. Like other GHRPs, HEX possesses also acute ACTH and cortisol-releasing activity similar to that of hCRH. Th e mechanisms underlying the stimulatory effect of GHRPs on hypothalamo pituitary-adrenal (HPA) axis are still unclear, although a CNS-mediate d action has been demonstrated. In 6 normal healthy young women (26-34 years) we studied the effects on ACTH and cortisol secretion of HEX ( 2.0 mu g/kg i.v. at 0 min) alone and preceded by dexamethasone (DEXA, 1 mg p.o. at 23.00 h on the previous night) or alprazolam (ALP, 0.02 m g/kg p.o. at -90 min), a benzodiazepine which binds to GABA receptors and possesses CRH-mediated inhibitory activity on HPA axis. ACTH and c ortisol secretion after saline administration as well as the GH respon se to HEX alone and preceded by DEXA. or ALP were also studied. HEX ad ministration elicited an increase in ACTH (peak vs, baseline, mean +/- SEM: 28.0 +/- 6.7 vs. 11.7 +/- 2.2 pg/ml, p < 0.05) and cortisol secr etion (162.6 +/- 15.0 vs. 137.7 +/- 12.6 mu g/l, p < 0.05). DEXA pretr eatment strongly inhibited basal ACTH (3.2 +/- 0.7 pg/ml, p < 0.01) an d cortisol levels (11.3 +/- 2.5 mu g/l, p < 0.001) and abolished the A CTH and cortisol responses to HEX(3.6 +/- 0.9 pg/ml, p < 0.01 and 10.7 +/-: 2.0 mu g/l, p < 0.001), respectively. On the other hand, ALP pre treatment did not significantly modify basal ACTH (7.9 +/- 2.0 pg/ml) and cortisol levels(127.6 +/- 14.5 mu g/l) but abolished the HEX-induc ed ACTH and cortisol secretions (8.6 +/- 2.4 pg/ml, p < 0.05 and 111.0 +/- 6.0 mu g/l, p < 0.05), respectively. ACTH and cortisol levels aft er HEX when preceded by ALP overlapped with those recorded during sali ne. HEX induced a clear GH response (peak at 15 min vs. baseline: 65.5 +/- 20.5 vs. 2.2 +/- 0.7 mu g/l, p < 0.03) which was blunted by ALP ( peak at 15 min: 21.5 +/- 5.5 mu g/l, p < 0.05) while it was not modifi ed by DEXA pretreatment(78.7 +/- 7.6 mu g/l). In conclusion, our prese nt data demonstrate that the ACTH-and cortisol-releasing effect of HEX is abolished by either dexamethasone or alprazolam, a benzodiazepine, which is even able to blunt the GH-releasing activity of the hexapept ide. These findings suggest that, in physiological conditions, the sti mulatory effect of GHRPs on HPA axis is sensitive to the negative gluc ocorticoid feedback and could be mediated by GABAergic mechanisms; the latter seem also involved in the GH-releasing activity of GHRPs.