LOW HEXARELIN DOSE AND PYRIDOSTIGMINE HAVE ADDITIVE EFFECT AND POTENTIATE TO THE SAME EXTENT THE GHRH-INDUCED GH RESPONSE IN MAN

OBJECTIVES Hexarelin (HEX) is a synthetic hexapeptide belonging to the growth hormone-releasing peptide (GHRP) family. The exact mechanism u nderlying the strong OH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the h ypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the OH-releasing activity of GH RPs in man, we investigated the effects of pyridostigmine, a cholinerg ic agonist which stimulates GH secretion by Inhibiting somatostatin re lease, on the GH response to various HEX doses. DESIGN We studied the GH release induced by various HEX doses (0.25, 0.5 and 2.0 mu g/kg iv) and pyridostigmine (PD, 120 mg po), both alone and coadministered. Th e interactions between the lowest HEX dose or PD and the maximally eff ective GHRH dose (1.0 mu g/kg iv) were also studied. SUBJECTS Six norm al male volunteers, aged 24-30 years, were studied. MEASUREMENTS Serum GH was measured in duplicate by immunoradiometric assay. RESULTS The GH response to HEX administration was dose-dependent. In fact, the GH response to 0.25 mu g/kg HEX (AUC, mean +/- SEM: 816.4 (235.6 mU/l/120 min) was lower, although not significantly, than that to 0.5 mu g/kg H EX (2154.6 +/- 491.6 mU/l/120 min), which, in turn, was lower (p<0.05) than that after 2.0 mu g/kg HEX (4819.2 +/- 668.0 mU/l/120 min). The GH rise after GHRH (1299.2 +/- 222.8 mU/l/120 min) was lower (P<0.05) than that after 2.0 mu g/kg HEX, but not different from the responses to either 0.25 or 0.5 mu g/kg HEX. PD induced a significant GH rise (5 59.0 +/- 129.8 mU/l/120 min, P<0.05 vs saline), similar to that after 0.25 mu g/kg HEX, and lower than those after both 0.5 and 2.0 mu g/kg HEX (P<0.05 and p<0.01, respectively) and GHRH (p<0.05). PO pretreatme nt enhanced the GH response to the lowest HEX dose (1961.4 +/- 253.8 m U/l/120 min, p<0.05) in an additive way, but failed to modify the GH r esponse to either 0.5 or 2.0 mu g/kg HEX (2753.6 +/- 444.6 and 5179.0 +/- 770.8 mU/l/120 min, respectively). Notably, the GH response to 0.2 5 mu g/kg HEX + PD was still lower (P < 0.05) than that to 2.0 mu g/kg HEX. PD pretreatment as well as 0.25 mu g/kg HEX truly potentiated th e GH response to GHRH to the same extent (4926.6 +/- 912.8 mU/l/120 mi n, p<0.05 and 5958.8 +/- 750.0 mU/l/120 min, p<0.05 respectively). The GH responses to PD + GHRH and 0.25 mu g/kg HEX + GHRH were similar to that after 2.0 mu g/kg HEX alone. CONCLUSIONS Our results demonstrate that pyridostigmine is able to enhance the GH response only to a very low dose Hexarelin which, in turn, potentiates the GHRH-induced GH ri se to the same extent as pyridostigmine. As there is evidence that GHR Ps do not inhibit hypothalamic somatostatin release, these findings ar e consistent with the hypothesis that they act by antagonizing somatos tatin activity and/or through unknown factors. On the other hand, thou gh there is evidence showing that GHRH activity is needed for GHRP act ion, our findings indicate that GHRPs act, at least partially, indepen dently of GHRH.