Growth Hormone-Releasing Hexapeptide Is a Potent Stimulator of Growth Hormone Gene Expression and Release in the Growth Hormone—Releasing Hormone—Deprived Infant Rat

Abstract

The growth hormone-releasing hexapeptide (GHRP-6) specifically stimulates growth hormonc (GH) secretion in several animal species and humans. The mechanism of action of GHRP-6 is largely unknown, although experimental evidence indicates that it may modulate growth hormone-releasing hormone (GHRH) and somatostatin actions at the pituitary or hypothalamic level. To gain more insight into the mechanism(s) of action of GHRP-6, we studied the infant rat, an animal model highly responsive to GH-releasing stimuli. In 14-d-old rats GHRP-6 (32-600 pgikg, LC.) induced a marked and dose-dependent rise in plasma GH concentrations, maximal stimulation occurring with the dose of 300 pgikg. Neither GHRH nor somatostatin antiserum prevented or modified the G H release elicited by GHRP-6. In pups passively immunized with GHRH antibodies, a 5-d treatment with GHRP-6 (80 pgikg, s.c., twice daily) completely counteracted the inhibitory effect of GHRH deprivation on G H mRNA expression. It1 GHRP-6 is a synthetic peptide that specifically stimulates growth hormone release in all species so far investigated (1-3). Although GHRP-6 has been shown to stimulate GH release irz virro from rat primary pituitary cell cultures (4, 5), it shows a far greater GH-releasing activity when administered in viva (6)(7)(8). These observations suggest that GHRP-6 stimulates GH secretion by acting Received December h, 1993 iitro GHRP-6 ( I W 7 and 10 " M) induced a small and transient stimulation of G H release from cultured pituitary cells. These results indicate the following: I) GHRP-6 is a potent stimulator of G H release in rat pups; 2) it stimulates G H gene expression in the GHRH-deprived pup; .?) during the neonatal period its action is not mediated by GHRH or somatostatin; and 4) its actions are not directed at the somatotrophs. (Pediatr Res 36: 169-174, 1994) Abbreviations GHRP-6, growth hormone-releasing hexapeptide GH, growth hormone GHRH, growth hormone-releasing hormonc GHRH-ab, antiserum against growth hormone-releasing hormone somatostatin-ab, antiserum against somatostatin NRS, normal rabbit serum on two sites, the pituitary and the hypothalamus. In keeping with these findings, receptor binding sites for GHRP-6 have been demonstrated in both tissues (9). Experimental evidence has indicated that GHRP-6 does not bind to the GHRH receptor (7) or activate adenylate cyclase (4). However, in vivo studies have shown that GHRP-6 potentiates the GH-releasing effect of GHRH when the peptides are coadministered into humans (8) or adult rats (lo), and passive immunization against GHRH attenuates the GH response to GHRP-6 (11). Overall, it appears that in vitro results imply independent mechanisms for GHRP-6 and GHRH at the level of the pituitary Supported by NIH Grants ROIDK3X324 and KO4DKOIX74.level (4, 6, 8), whereas in llivo findings suggest thatThe present work is part of the program of the "Gruppo per lo studio dellr modificazioni della secrezione di ormone somatotropo nelle varie fasi della vita. GHRP-6 may modulate GHRH or somatostatin functi...

Six-week treatment with hexarelin in young dogs: evaluation of the GH responsiveness to acute hexarelin or GHRH administration, and of the orexigenic effect of hexarelin

“…A similar pattern had been demonstrated in the early phases of hexarelin administration in old dogs, in which, however, even during the off-periods of the peptide treatment, baseline GH concentrations remained higher than pretreatment values (18). In infant GHRH-deprived rats, treatment with hexarelin for 3 or 5 days increased pituitary GH mRNA (35), whereas, given for 5-10 days to young 'intact' adult rats, it was ineffective in this context (36). Also worth noting in this context is that, in young GHRH-deprived rats, a 10-day treatment with hexarelin increased the expression of its own receptors in the pituitary (R Nass & A Torsello, unpublished results).…”

“…In our present study, baseline GH concentrations were not different at the three periods of hexarelin challenge, which would indicate that the ability of GHRP to prime the pituitary was confined to GH release, and did not involve GH synthesis. The enhanced GH responsiveness to hexarelin, present in both rats (35) and dogs (this study and (18)) during the initial phase of treatment has not been reported previously in humans (27,37,38). Although difficult to interpret, this discrepancy may be due to the higher sensitivity of humans than rats and dogs to the GH-releasing activity of the GHRPs, an event for which no clear explanation is available at present.…”

Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion

“…Unlike GHRH, GHS and ghrelin induce GH gene expression only upon prolonged delivery to the infantile rat in vivo or to somatotropes in vitro (42,54). Thus model parameters in the adult animal include GHS-dependent stimulation of GH secretion but not de novo GH synthesis.…”

Ghrelin-induced GH secretion in domestic fowl in vivo and in vitro

“…The minimally effective dose of ghrelin in chickens in vitro (10 9 M) is, however, higher than that (10 11 M) required to provoke GH release in some studies with rat pituitary cells (Yamazaki et al 2002), although it is comparable with that in other studies (Kojima et al 1999). Other GH secretagogue receptor agonists also promote GH release from rat pituitary tissues (Locatelli et al 1994) and a pituitary site of ghrelin action is undoubtedly involved, despite the finding by Pinilla et al (2003) that ghrelin was ineffective in inducing GH release from the pituitaries of prepubertal rats at concentrations of 10 9 to 10 7 M, concentrations that were effective for GHRH.…”