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His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂ (GHRP-6) is a synthetic peptide unrelated to any known hypothalamic-releasing hormone including growth hormone-releasing hormone (GHRH). Interestingly, this peptide induces a dose-related increase in plasma GH levels in all species tested so far. The aim of this study was to investigate the action of GHRP-6 alone or in combination with GHRH on GH release in dogs. In addition, the activation or blockade of endogenous cholinergic tone and -1 adrenoceptors on GHRP-6-stimulated GH secretion was assessed.

In adult Beagle dogs (n = 10), GHRP-6 (90 µg i.v.) increased basal GH levels from 2·6 ± 1·5 to 14·4 ± 3·1 µg/l (mean ± S.E.M.) after 15 min. GHRH (50 µg i.v.) induced a GH peak of 9·7 ± 2·2 µg/l at 15 min. The combined administration of GHRP-6 and GHRH strikingly potentiated canine GH release with a peak of 54 ± 9·0 µg/l (P <0·01). Pretreatment with the cholinergic agonist pyridostigmine (30 mg per os) increased GHRP-6-stimulated GH secretion (37·9 ± 10·1 µg/l P <0·05), while the muscarinic blocker atropine (100 µg i.v.) completely abolished (GH peak lower than 2 µg/l) the stimulatory action of GHRP-6. On the other hand, administration of the -2 adrenergic agonist clonidine (4 pg/kg i.v.) increased basal plasma GH levels without affecting GH responses to GHRP-6. Finally, while the -1 adrenergic agonist methoxamine (5 mg i.v.) did not significantly increase GH responses to GHRP-6, administration of the -1 adrenoceptor antagonist prazosin (20 mg i.v.) reduced GHRP-6-induced GH secretion (area under curve, 206 ± 39 vs 557 ± 172, P <0·05).

In summary, the synergistic effect of the combined administration of maximal doses of GHRP-6 and GHRH suggests that these two peptides act through different mechanisms. The finding that cholinergic drugs were able to modulate the GH secretion elicited by GHRP-6 argues against the hypothesis that such a peptide acts by influencing hypothalamic somatostatin release and suggests that it acts directly at the pituitary level. Finally, the unexpected lack of effect of clonidine and the inhibitory effect of prazosin on GHRP-6-induced GH secretion suggests that the role of -adrenergic pathways in GH secretion is more complex than previously thought.

Journal of Endocrinology (1993) 138, 211–218