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 underlying the strong OH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the hypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the OH-releasing activity of GHRPs in man, we investigated the effects of pyridostigmine, a cholinergic agonist which stimulates GH secretion by Inhibiting somatostatin release, 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. The interactions between the lowest HEX dose or PD and the maximally effective GHRH dose (1.0 mu g/kg iv) were also studied. SUBJECTS Six normal 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/120min) was lower, although not significantly, than that to 0.5 mu g/kg HEX (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 (559.0 +/- 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 pretreatment enhanced the GH response to the lowest HEX dose (1961.4 +/- 253.8 mU/l/120 min, p<0.05) in an additive way, but failed to modify the GH response 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 0.25 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 the GH response to GHRH to the same extent (4926.6 +/- 912.8 mU/l/120 min, 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 rise to the same extent as pyridostigmine. As there is evidence that GHRPs do not inhibit hypothalamic somatostatin release, these findings are consistent with the hypothesis that they act by antagonizing somatostatin activity and/or through unknown factors. On the other hand, though there is evidence showing that GHRH activity is needed for GHRP action, our findings indicate that GHRPs act, at least partially, independently of GHRH.