EFFECT OF GROWTH-HORMONE (GH)-RELEASING HORMONE (GHRH), ATROPINE, PYRIDOSTIGMINE, OR HYPOGLYCEMIA ON GHRP-6-INDUCED GH SECRETION IN MAN

His-DTrp-Ala-Trp-DPhe-Lys-NH2 (GHRP-6) is a synthetic compound that re leases GH in a dose-related and specific manner in several species, in cluding man. To further characterize the effects and mechanism of acti on of GHRP-6 on GH secretion, we assessed in normal man plasma GH resp onses to that hexapeptide 1) alone and in combination with exogenous G H-releasing hormone (GHRH) administration, 2) in a state of high endog enous somatostatinergic tone after atropine administration, and 3) in a state of low endogenous somatostatinergic tone induced by the cholin ergic receptor agonist drug pyridostigmine or after insulin-induced hy poglycemia. We found a similar increase in plasma GH levels after the administration of either GHRP-6 (1 mug/kg) or GHRH (1 mug/kg); the are as under the curve (AUC) were (mean +/- SEM) 973 +/- 181 and 821 +/- 1 39, respectively. After combined GHRP-6 and GHRH administration, GH re sponses were considerably greater than those after either compound alo ne (4412 +/- 842; P < 0.01). Administration of the cholinergic recepto r antagonist atropine (1 mg, im) completely prevented the GH responses to GHRP-6 (area under the curve, 103 +/- 14 vs. 815 +/- 156, respecti vely). On the other hand, pyridostigmine, a cholinergic agonist, sligh tly increased GH responses to GHRP-6 (P < 0.01 when comparing the AUC after pyridostigmine administration of 1571 +/- 151 and the AUC after administration of GHRP-6 alone of 815 +/- 156). Finally, combined GHRP -6 and insulin administration induced a much greater increase in plasm a GH levels (AUC, 4047 +/- 327) than insulin alone (1747 +/-229; P < 0 .05) or GHRP-6 alone (1248 +/- 376; P < 0.05). Our results lend suppor t to the view that GHRP-6-induced GH secretion is exerted through a no n-GHRH-dependent mechanism. Furthermore, the fact that enhancement of somatostatinergic tone with atropine completely prevented the GH respo nses to GHRP-6, while pyridostigmine and insulin-induced hypoglycemia, which increased plasma GH levels by inhibiting hypothalamic somatosta tin release, increased the same response suggest that although GHRP-6- induced GH secretion is dependent on the endogenous somatostatinergic tone, the stimulatory effect of GHRP-6 on plasma GH levels is not medi ated by a change in hypothalamic somatostatinergic tone.