INFLUENCE OF ENDOGENOUS CHOLINERGIC TONE AND ALPHA-ADRENERGIC PATHWAYS ON GROWTH-HORMONE RESPONSES TO HIS-D-TRP-ALA-TRP-D-PHE-LYS-NH2 IN THE DOG

HiS-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6) is a synthetic peptide unrela ted to any known hypothalamic-releasing hormone including growth hormo ne-releasing hormone (GHRH). Interestingly, this peptide induces a dos e-related increase in plasma GH levels in all species tested so far. T he 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 activ ation or blockade of endogenous cholinergic tone and alpha-1 adrenocep tors, on GHRP-6-stimulated GH secretion was assessed. In adult Beagle dogs (n = 10), GHRP-6 (90 mug i.v.) increased basal GH levels from 2.6 +/- 1.5 to 14.4 +/- 3.1 mug/l (mean +/- S.E.M.) after 15 min. GHRH (5 0 mug i.v.) induced a GH peak of 9.7 +/- 2.2 mug/l at 15 min. The comb ined administration of GHRP-6 and GHRH strikingly potentiated canine G H release with a peak of 54 +/- 9.0 mug/l (P<0.01). Pretreatment with the cholinergic agonist pyridostigmine (30 mg per os) increased GHRP-6 -stimulated GH secretion (37.9 +/- 10.1 mug/l P<0.05), while the musca rinic blocker atropine (100 mug i.v.) completely abolished (GH peak lo wer than 2 mug/l) the stimulatory action of GHRP-6. On the other hand, administration of the alpha-2 adrenergic agonist clonidine (4 mug/kg i.v.) increased basal plasma GH levels without affecting GH responses to GHRP-6. Finally, while the a-I adrenergic agonist methoxamine (5 mg i.v.) did not significantly increase GH responses to GHRP-6, administ ration of the a-I adrenoceptor antagonist prazosin (20 mg i.v.) reduce d GHRP-6-induced GH secretion (area under curve, 206 +/- 39 vs 557 +/- 172, P<0.05). In summary, the synergistic effect of the combined admi nistration of maximal doses of GHRP-6 and GHRH suggests that these two peptides act through different mechanisms. The finding that cholinerg ic drugs were able to modulate the GH secretion elicited by GHRP-6 arg ues against the hypothesis that such a peptide acts by influencing hyp othalamic somatostatin release and suggests that it acts directly at t he pituitary level. Finally, the unexpected lack of effect of clonidin e and the inhibitory effect of prazosin on GHRP-6-induced GH secretion suggests that the role of alpha-adrenergic pathways in GH secretion i s more complex than previously thought.