title: Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat.
abstract: We have reported Hexarelin (HEXA), an analog of growth hormone-releasing peptide 6 (GHRP-6), potently stimulates growth hormone (GH) secretion in infant and adult rats. This study was undertaken to further investigate Hexarelin's mechanisms of action. In 10-day-old pups, treatments with HEXA (80 micrograms/kg, b.i.d.) for 3-10 days significantly enhanced, in a time-related fashion, the GH response to an acute HEXA challenge. Qualitatively similar effects were elicited in pups passively immunized against growth hormone-releasing hormone (GHRH) from birth. In adult male rats, a 5-day pretreatment with HEXA (150 micrograms/kg, b.i.d.) did not enhance the effect of the acute challenge, and the same pattern was present after a 5-day pretreatment in male rats with surgical ablation of the mediobasal hypothalamus (MBH-ablated rats). In addition, in adult sham-operated rats, Hexarelin (300 micrograms/kg, i.v.) induced a GH response greater (p < 0.05) than that induced by GHRH (2 micrograms/kg, i.v.). However, in MBH-ablated rats 7 days after surgery, GHRH was significantly (p < 0.05) more effective than HEXA, and 30 days after surgery HEXA and GHRH evoked similar rises of plasma GH. Finally, the in vitro Hexarelin (10(-6) mol/l) effect was transient while GHRH (10(-8) mol/l) induced a longer lasting and greater GH release. Three different mechanisms, not mutually exclusive, are postulated for Hexarelin stimulation of GH secretion in vivo: a direct action on the pituitary, though of minor relevance; an indirect action that involves release of GHRH, of relevance only in adult rats; and an action through the release of a still unknown hypothalamic "factor", which in infant and adult rats elicits GH release acting sinergistically with GHRH.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Torsello
authors.forename: R
authors.initials: R
authors.lastname: Grilli
authors.forename: M
authors.initials: M
authors.lastname: Luoni
authors.forename: M
authors.initials: M
authors.lastname: Guidi
authors.forename: M C
authors.initials: MC
authors.lastname: Ghigo
authors.forename: W B
authors.initials: WB
authors.lastname: Wehrenberg
authors.forename: R
authors.initials: R
authors.lastname: Deghenghi
authors.forename: E E
authors.initials: EE
authors.lastname: Müller
authors.forename: V
authors.initials: V
authors.lastname: Locatelli
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D009842:Oligopeptides; C086184:hexarelin; D013006:Growth Hormone