ABSTRACT
In the early 1980s, growth hormone (GH)-releasing peptide (GHRP-6) was emerging as the first identified number of a class of synthetic GH secretagogues (GHSs), the actions of which were selective and potent for GH secretion (1). GHRP-6 stimulates GH secretion from pituitary cells in vitro, providing evidence for a direct pituitary action (1) and the GH-releasing mechanism appears to differ from that of the endogenous GH-releasing factor (GRF; 2,3). By the late 1980s-early 1990s there was a great deal of circumstantial evidence that GHRP-6 may also act within the central nervous system (CNS) to stimulate GH secretion. For example, when administered together, the effects of GRF and GHRP-6 on GH secretion were merely additive in vitro (in pituitary perfusion experiments and in cell culture), but displayed an enormous synergy in vivo (4); these differences could not be explained by an interaction of these peptides at the pituitary level alone. Rather, it was suggested that the central actions of GHRP-6 may include the release of an unknown hypothalamic-releasing factor (a "U-factor") into the portal blood; according to this hypothesis, the U-factor
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would act together with GRF to stimulate GH secretion from the pituitary (4). That GHRP-6 may act centrally to alter the output of the hypothalamic GRFsomatostatin GH pulse generator was first suggested by Clark and colleagues (5). They argued that part of the GH-releasing mechanism of GHRP-6 is likely to include increased GRF release, because the GHRP-6-induced GH response was attenuated in rats passively immunized with GRF antiserum. Furthermore, they suggested that GHRP-6 may alter somatostatin secretion, because it disrupted the cyclic changes in GH release following regular injections of GRF (a response that has been attributed to cyclic changes in somatostatin secretion).
