METABOLIC MODULATION OF THE GROWTH HORMONE-RELEASING ACTIVITY OF HEXARELIN IN MAN

Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new potent s ynthetic growth hormone (GH)-releasing hexapeptide. The mechanism of a ction of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypotha lamus. To elucidate its mechanism of action in man, we studied the int eraction of hexarelin with glucose and free fatty acids (FFA), two met abolic factors known to inhibit both basal and GH releasing hormone (G HRH) stimulated GH secretion. Glucose is thought to inhibit GH secreti on via stimulation of endogenous somatostatin release, whereas FFA cou ld also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a max imal dose (2 mu g/kg intravenously [IV]) of hexarelin or GHRH in six n ormal men. Hexarelin elicited a clear-cut GH response (mean +/- SEM; p eak, 62.6 +/- 8.0 mu g/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 +/- 2.4 mu g/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almo st abolished the GH response to GHRH (peak, 5.6 +/- 0.9 mu g/L, P < .0 1) while only blunting the somatotrope response to hexarelin (peak, 38 .4 +/- 7.9 mu g/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 +/- 1.0 mu g/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 +/- 4.5 mu g/L, P < .05). This study shows that hexarelin releases mor e GH than GHRH and that it is more resistant than GHRH to the inhibito ry effect of glucose or FFA. Its resistance to inhibitory influences c ould be due to antagonism of somatostatinergic activity within the hyp othalamus or directly at the pituitary level, although unknown mechani sms cannot be ruled out. Copyright (C) 1995 by W.B. Saunders Company