Hexarelin Stimulation of Growth Hormone Release and mRNA Levels in an Infant and Adult Rat Model of Impaired GHRH Function

Abstract

Hexarelin, a GH-releasing peptide, is an effective GH secretagogue in man and a variety of experimental animals. In the present study, we sought to characterize the effects of short-term Hexarelin treatment on GH release and GH mRNA levels in infant and young-adult rats and in rats of either age passively immunized with an antiserum against GHRH (GHRH-Ab). Hexarelin (80 µg/ kg, b.i.d. s.c), administered for 3, 5 or 10 days to 8-, 6- and 1-day-old rats, respectively, induced a progressive enhancement of the plasma GH rise elicited by a subsequent acute Hexarelin (80 µg/kg s.c.) challenge when pups were 10 days old. As expected, GHRH-Ab treatment decreased GH concentrations in 10-day-old pups. In GHRH-Ab-treated pups, Hexarelin administration for 3-10 days significantly enhanced the GH response to the acute Hexarelin injection, though the mean plasma GH values remained significantly lower than in the respective control group. Hexarelin treatment did not alter GH mRNA levels in control pups. In GHRH-Ab-treated pups Hexarelin treatment for 3 and 5 days, but not 10 days, restored GH mRNA levels to control values. In young-adult male rats, regardless of antiserum treatment, Hexarelin administration for 5 or 10 days significantly suppressed the GH response to a subsequent acute challenge with the peptide. Yet, 5-10 days of Hexarelin treatment did not alter GH mRNA in control young-adult rats. In adult rats GHRH-Ab also decreased GH mRNA levels, but 10 days of Hexarelin treatment were necessary to return GH mRNA back to normal levels. These results indicate that: (1) the effects of Hexarelin on GH release and GH mRNA levels may be unrelated events; (2) deprivation of GHRH function discloses the ability of Hexarelin to stimulate GH mRNA levels; (3) age plays a crucial role in setting the pituitary responsiveness to short-term Hexarelin treatment, and (4) the different ability of Hexarelin to stimulate GH release and GH synthesis in neonatal and young-adult rats may have clinical relevance in the chronic administration of the peptide.

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).…”

Growth Hormone-Independent Cardioprotective Effects of Hexarelin in the Rat1

“…However, previous studies indicated that the GH-secreting activity of hexarelin was largely impaired in the GHD rat model (8). Like other GHSs, hexarelin requires the presence of endogenous GHRH for maximal stimulation of GH secretion (8,9), because passive immunization against GHRH blunts hexarelin-induced GH secretion (10).…”

Hexarelin Modulates the Expression of Growth Hormone Secretagogue Receptor Type 1a mRNA at Hypothalamic and Pituitary Sites

“…The antiserum against GHRH (GHRH-Ab; a generous gift of Dr. William B. Wehrenberg) had been fully tested and found to be effective in blunting body growth [25, 26, 27, 31]. Based on those studies, the dose of 100 µl/rat for 10-day-old rats and 500 µl/rat for young adult rats were chosen since they reproducibly resulted in maximal inhibition of GH secretion.…”

“…The length of treatment with hexarelin and GHRH was chosen based on previous experiments [31]in which we demonstrated that 5 and 10 days of hexarelin treatment were needed to stimulate an increase in GH mRNA in GHRH-deficient neonatal and young adult rats, respectively.…”

“…Thus, with the aim of better understanding the interrelationship between GHRH and the GHS-R1a, in the present study, the effects of passive immunization against GHRH were also studied. Some of the existing studies suggest that the GH-releasing effects of GHSs are age dependent [31, 32]and GHS-R expression is developmentally regulated [33, 34]; hence, the experiments were performed in 10-day-old infant, and young adult rats.…”