Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.

Abstract

L-692,429, a benzolactam derivative, stimulated GH release from rat primary pituitary cells in a dose-dependent manner. The concentration of L-692,429 required for half-maximal stimulation were 59.6 +/- 7.3 nM. Under the same conditions, GHRP-6 and GRF had EC50 values of 10.3 +/- 1.9 nM and 0.47 +/- 0.09 nM, respectively. L-692,428, the enantiomer of L-692,429, was inactive at a concentration as high as 2 microM. Like GHRP-6, L-692,429 had no effect on intracellular cAMP level; however, it synergized with GRF to further increase not only the accumulation of cAMP but also the release of GH. The magnitude of GH release stimulated by maximal concentrations of L-692,429 and GHRP-6 was comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause additional GH release when compared with either secretagogue alone. The L-692,429-stimulated GH release was completely inhibited by 20 nM somatostatin. To our knowledge, L-692,429 is the first non-peptidyl GH secretagogue which has a direct effect on the release of growth hormone from rat primary pituitary cells. Its effect is most likely mediated through a mechanism which is similar to that of GHRP-6.

Effect of Growth Hormone (GH)-Releasing Peptide (GHRP) on the Release of GH from Cultured Anterior Pituitary Cells in Cattle.

“…GH release from rat pituitary cells induced by GHRP was observed after 15 min, but not after 4 h [11]. Concerning the direct action of GHRP in inducing GH release from cultured pituitary cells, the present results in cattle are in agreement with the previous reports in rats [6,8,11,12,21]. This study showed that GHRH (10-' M) was significantly more potent than GHRP (10-~ M) in stimulating bovine GH release in vitro.…”

Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland

“…These data supported the hypothesis that an endogenous sGHS-like ligand exists and is involved in the control of GH secretion . In fact, the presence of GHS receptors (sGHS-R) in the pituitary gland and hypothalamus agrees with data for animals and humans showing that the GH-releasing activity of sGHS is the result of direct stimulation of somatotroph cells (Smith et al 1993, Akman et al 1993, Wu et al 1994 and of a more important action at the hypothalamic level , Fletcher et al 1994, Fairhall et al 1995, Hickey et al 1996. The mechanisms of action underlying the GH-releasing activity of peptidyl and non-peptidyl sGHS seem to involve the antagonism of somatostatinergic pathways at both the pituitary and hypothalamic level as well as the stimulation of GHRH-secreting neurones (Conley et al 1995, Hickey et al 1996.…”

“…These synthetic GH secretagogues (sGHS), although modelled from Met-enkephalins, have lost the opioid activity and stimulate GH secretion of pituitary somatotroph cells both in vitro and in vivo in a variety of species, including rat, pig and human (Momany et al 1981, Bowers et al 1984, Bowers 1993, Ghigo et al 1994, Arvat et al 1995. Since all these peptides have an oral bioavailability lower than 1%, a number of non-peptidyl sGHS 429,653 and MK 0677), with structures more amenable to chemical modification and optimization of oral bioavailability, have been developed and studied in both animals and man (Cheng et al 1993, Gertz et al 1993, Smith et al 1993, Jacks et al 1994, Chang et al 1995. Among them, the spiroindoline derivative, MK 0677, proved to be the strongest stimulator of GH secretion (Patchett et al 1995).…”

Ghrelin, an endogenous growth hormone secretagogue with diverse endocrine and nonendocrine effects

“…21,36,37,43 Messenger RNA encoding GHS-R 1a has been detected in the pituitary gland, indicating that GHSs can act directly on somatotrophs to stimulate GH release. This is in accordance with an earlier observation 44 that GHSs are able to directly stimulate GH release from rat pituitary cells in vitro. The hypothalamic localization of the GHS-R 1a, especially in the supraoptic and paraventricular nuclei, supports the notion that GHSs may also indirectly regulate GH release by interacting with GHRH-producing neurons, somatostatin-producing neurons, or both, in the hypothalamus.…”