Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat.
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.
Torsello
A
A
Department of Pharmacology, School of Medicine, University of Milan, Italy.
Grilli
R
R
Luoni
M
M
Guidi
M
M
Ghigo
M C
MC
Wehrenberg
W B
WB
Deghenghi
R
R
Müller
E E
EE
Locatelli
V
V
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
D009842:Oligopeptides; C086184:hexarelin; D013006:Growth Hormone