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 micrograms/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 micrograms/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.