MODULATION OF GROWTH HORMONE-RELEASING ACTIVITY OF HEXARELIN IN MAN

Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new syntheti c growth hormone (GH)-releasing hexapeptide. The mechanism of action o f hexarelin in man is not fully elucidated. As for other GH-releasing peptides, an action on both the pituitary gland and the hypothalamus h as been hypothesized. In the present study, we evaluated the modulatio n of GH-releasing activity of hexarelin in man. In a first experiment conducted on 6 healthy male volunteers, we studied the interaction of the maximally effective intravenous dose of hexarelin (2 mu g/kg i.v.) with GH-releasing hormone (GHRH, 2 mu g/kg i.v.) and somatostatin (2 mu g/kg/h i.v.). In a second experiment involving another 6 male subje cts, we evaluated the interaction of hexarelin with neuroactive substa nces, such as pirenzepine (0.6 mg/kg i.v.), pyridostigmine (120 mg p.o .) and arginine (0.5 g/kg i.v.), thought to modulate endogenous somato statin secretion. Hexarelin induced a higher increase in GH levels as compared to GHRH (integrated output calculated as area under the curve AUC(0-120) 4,693 +/- 691 vs. 1,494 +/- 102 mu g.min/l, p < 0.01). Coa dministration of hexarelin and GHRH produced a higher GH response than hexarelin alone (AUC(0-120) 7,395 +/- 450 mu g.min/l, p < 0.05). Soma tostatin abolished the GH response to GHRH (AUC(0-120) 363 +/- 89 mu g .min/l, p < 0.01), while it only blunted that to hexarelin (AUC(0-120) 1,314 +/- 297 mu g.min/l, p < 0.05). Pirenzepine blunted the GH respo nse to hexarelin (AUC(0-120) 1,931 +/- 446 vs. 4,586 +/- 674 mu g.min/ l, p < 0.05) while pyridostigmine and arginine did not modify the GH r esponse to the hexapeptide (AUC(0-120) 5,179 +/- 771 and 4,743 +/- 774 mu g.min/l). Thus, the GH-releasing activity of hexarelin is greater than that of GHRH and is even enhanced by the neurohormone. Hexarelin differs from GHRH in that its effect is only blunted by exogenous soma tostatin or pirenzepine and is not potentiated by pyridostigmine or ar ginine. These results indicate that, in man, hexarelin and GHRH may ha ve different mechanisms of action and that the potent GH-releasing act ivity of hexarelin is partially refractory to modulation by somatostat in.