Hexarelin, a novel GHRP-6 analog, stimulates growth hormone (GH) release in a GH-secreting rat cell line (GH(1)) insensitive to GH-releasing hormone

Previous studies demonstrated that GHRP-6 has modest GH-releasing activity in primary pituitary cell monolayer cultures. However, the effects of this peptide have always been tested on cells very sensitive to GHRH. We have previously reported that GHRH is unable to stimulate GH secretion in the GH(1) rat tumor cell line. The aim of the study was to assess for the first time the effect on GH secretion of the GHRP-6 analog, hexarelin, in the GH(1) cells; moreover, we investigated the potential involvement of GHRH in the effects of hexarelin in the GH(1) rat cell line. The GHRP-6 analog hexarelin (0.01-1 mu M) significantly stimulated GH release in both normal and GH(1) rat cells. The greatest GH-releasing effect of hexarelin was observed with the 1 mu M dose both in GH(1) (155+/-25% vs. control wells) and in normal rat pituitary cells (185+/-23% vs. control wells). GHRH significantly stimulated GH secretion in normal rat somatotrophs (3-fold increase). In this latter cell model, GHRH and hexarelin were demonstrated to have additive stimulatory effects on GH secretion. Conversely, GHRH did not affect hexarelin-stimulated GH release in GH(1) cells at any of the doses used. Finally, 8Br-cAMP significantly stimulated GH secretion in both normal rat and GH(1) cells. These results provide in vitro evidence that non-GHRH-mediated pathways for GHRP action exist. Moreover, the observation that cells not sensitive to GHRH can be significantly stimulated by hexarelin strongly suggests that GHRPs and GHRH have two distinct sites and modes of action at the pituitary level. (C) 1997 Elsevier Science B.V.