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± 32

2.4 ± 0.2

aThe in vitro studies (mean of 9 ± SEM) were performed using the pituitary incubate assay and the in vivo studies (mean of 10 ± SEM) using rats treated with 50 ^g [His1Lys6]GHRP daily for 25 d sc at 1500 h. The aforementioned acute study was performed 24 h after the last injection of the peptide. Blood for hormone determinations was collected at +15 min after injection of saline or the peptide. Reproduced with permission from ref. 11.

aThe in vitro studies (mean of 9 ± SEM) were performed using the pituitary incubate assay and the in vivo studies (mean of 10 ± SEM) using rats treated with 50 ^g [His1Lys6]GHRP daily for 25 d sc at 1500 h. The aforementioned acute study was performed 24 h after the last injection of the peptide. Blood for hormone determinations was collected at +15 min after injection of saline or the peptide. Reproduced with permission from ref. 11.

Between 1978 and 1980, four different major types of GHRPs were developed, including DTrp2 (Table 2) (6-9). Despite increased potency, none of these small peptides were active in vitro. Noteworthy was that GH releasing activity was strongly related to the position and stereochemistry of Trp residues. A series of detailed conformational studies by Momany helped to guide the development of the DTrp2AlaLTrp4 sequence of GHRP, which was valuable in the development of the in vitro and in vivo active GHRPs, i.e., GHRP-6, -1, -2 (10-15). From desensitization crossover studies, and from synergistic or additive effects of the GHRPs, evidence strongly indicated that the same receptor and molecular mechanism was activated by structurally different GHRPs. A surprising exception, which suggested finding the possibility of a GHRP receptor subtype, was that in sheep pituitary cell cultures where GHRP-2, but not GHRP-6, raised intracellular cAMP levels; furthermore, a GHRH antagonist inhibited the GHRP-2 GH response (16).

In 1976-77, early results of DTrp2 were considered indicative that this pentapeptide may be acting via the putative GHRH receptor (4,9). Subsequent studies with GHRP-6 in 1980-81 reinforced the notion. However, following the isolation of a native growth hormone releasing factor and its structural elucidation in 1982, it became apparent that the releasing factor was a natural growth hormone releasing hormone (GHRH) and that GHRP acted via a different receptor. Because GHRPs had characteristics of hypophysio-tropic hormones, it was proposed in 1984 that they might mimic another native hormone different from GHRH (11).

Results in Table 3 show that GHRP-6 specifically releases GH in vitro and in vivo (11). The in vivo results were obtained after immature female rats were injected with GHRP-6 or saline once or twice daily subcutaneously (sc) for 25 d. After chronic administration of GHRP-6, the GH response and specificity as well as the increase in body weight gain were maintained (Table 3 and Fig. 2).

Between 1981-88, the interrelationship between the actions of GHRP-6, GHRH, and opiates or opiate peptides were studied (10,17-28). Desensitization crossover studies of these three GH-releasing secretagogues revealed the independent action of all three peptides because when the GH response of one secretagogue was desensitized the other one was fully active. When these secretagogues were combined and administered to rats GH was released synergistically, and when all three were administered together, the

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