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 acti vity in primary pituitary cell monolayer cultures. However, the effect s of this peptide have always been tested on cells very sensitive to G HRH. We have previously reported that GHRH is unable to stimulate GH s ecretion 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 an alog, hexarelin, in the GH(1) cells; moreover, we investigated the pot ential involvement of GHRH in the effects of hexarelin in the GH(1) ra t cell line. The GHRP-6 analog hexarelin (0.01-1 mu M) significantly s timulated 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 bot h in GH(1) (155+/-25% vs. control wells) and in normal rat pituitary c ells (185+/-23% vs. control wells). GHRH significantly stimulated GH s ecretion in normal rat somatotrophs (3-fold increase). In this latter cell model, GHRH and hexarelin were demonstrated to have additive stim ulatory effects on GH secretion. Conversely, GHRH did not affect hexar elin-stimulated GH release in GH(1) cells at any of the doses used. Fi nally, 8Br-cAMP significantly stimulated GH secretion in both normal r at and GH(1) cells. These results provide in vitro evidence that non-G HRH-mediated pathways for GHRP action exist. Moreover, the observation that cells not sensitive to GHRH can be significantly stimulated by h exarelin strongly suggests that GHRPs and GHRH have two distinct sites and modes of action at the pituitary level. (C) 1997 Elsevier Science B.V.