Do growth hormone-releasing peptides act as ghrelin secretagogues?
NN703 is an orally active and selective growth hormone secretagogue (GHS) that was derived from growth hormone-releasing peptide-1(GHRP-1) via ipamorelin by a peptidomimetic approach and has now entered into phase II clinical trials. When the disposition in rats of NN703 and GHRP-6 was studied using whole-body autoradiography following administration of an iv dose of radiolabeled material, we found that a substantial amount of these secretagogues accumulate in the glandular part of the stomach. Because this is the site of synthesis and secretion of ghrelin, the endogenous GHS, we investigated the effect of resection of the gastrointestinal (GI) tract on growth hormone (GH) release induced by GHRP-6. This procedure significantly attenuated the GH secretion response by 60-70%. By contrast, the effect of GH-releasing hormone on GH release was not inhibited. The binding of GHRPs to the glandular part of the stomach and the blunted GH response to GHRP-6 following resection of the GI tract suggest a role for ghrelin as a mediator of part of the GH-releasing effect of GHRPs.
Ahnfelt-Rønne
I
I
Novo Nordisk A/S, Discovery & Preclinical Development, Maalov, Denmark. iar@novo.dk
Nowak
J
J
Olsen
U B
UB
D000818:Animals; D001345:Autoradiography; D004151:Dipeptides / Q000494:pharmacology*; D005743:Gastrectomy; D005753:Gastric Mucosa / Q000378:metabolism; D054439:Ghrelin; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D007457:Iodine Radioisotopes; D009842:Oligopeptides / Q000494:pharmacology*; D036361:Peptide Hormones; D010455:Peptides / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects / Q000601:surgery; D013997:Time Factors
D004151:Dipeptides; D054439:Ghrelin; D007457:Iodine Radioisotopes; D009842:Oligopeptides; D036361:Peptide Hormones; D010455:Peptides; C041048:growth hormone releasing hexapeptide; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C120631:tabimorelin