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18046 ± 2800d

39134 ± 1730d

21088 ± 4468d

^Reproduced with permission from ref. 26.

bH and P from 26-d-old female rats. Values are the mean of 9 determinations. Each A value was calculated from three consecutive 1 h incubation periods (I3-I5) minus basal release of GH during the preincubation period.

^Reproduced with permission from ref. 26.

bH and P from 26-d-old female rats. Values are the mean of 9 determinations. Each A value was calculated from three consecutive 1 h incubation periods (I3-I5) minus basal release of GH during the preincubation period.

peptide, dermorphin. These studies led to the conclusion that GHRP and the opiate GH responses were dependent on endogenous GHRH and since pretreatment with SRIF antiserum augmented the response of GHRP-6 and GHRH, neither one inhibited the release of SRIF. In contrast, because the SRIF antiserum pretreatment was without an effect on the GH response of the opiates, the opiates did appear to inhibit the release of endogenous SRIF. Thus, each of these three GH secretagogues—GHRP, GHRH, and the opiate peptide—was considered to release GH by a different mechanism and, in addition, the mechanisms or actions were complementary in releasing GH. Importantly, although response to the GHRP is dependent on endogenous GHRH, GHRH apparently plays a permissive role.

In addition to a direct action on the pituitary gland, a direct hypothalamic action of GHRP has been demonstrated (Table 4) (26). In three different in vitro assay systems, pituitary incubate, dispersed pituitary monolayer cell culture, and perifusion of pituitary cells, the GH response to GHRP+GHRH was essentially additive or only slightly syner-gistic («30%), and thus the direct pituitary action of the two peptides was insufficient to account for the magnitude of the synergism induced by GHRP+GHRH (26). Even when the in vitro GHRP+GHRH results in the pituitary cell culture and incubate assay were obtained under different experimental conditions and the time of the GH response was varied the effect on GH release was essentially additive. Other investigators have found synergism in vitro, but this has been the exception (29).

The in vivo synergistic release of GH induced by GHRP+GHRH has been a hallmark of the GHRP effect on GH release in that it occurs in multiple animal species and in humans of all ages and both sexes. The exact mechanism(s) involved has not been elucidated. The fact that synergism has been such a consistent finding, even at very low dosages (»2 ^g) in humans, has led us to believe that understanding how this occurs will substantially aid in elucidation of the action of GHRP especially on the hypothalamus. Examples of the synergistic GH response induced by GHRP-6+GHRH in male and female rats, rhesus monkeys, and cows are recorded in Table 5.

Table 5 Synergistic GH Response^

Immature rat

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