CONSISTENT GH RESPONSES TO REPEATED INJECTIONS OF GH-RELEASING HEXAPEPTIDE (GHRP-6) AND THE NONPEPTIDE GH SECRETAGOGUE, L-692,585

GH release is normally stimulated by the naturally occurring GH-releas ing factor (GRF). However, smaller GH-releasing peptides (GHRPs) and n on-peptide analogues have been described which stimulate GH release in animals and man. Although these compounds release GH in vitro, their in vivo activity in conscious animals has proved more difficult to stu dy since the GH responses are variable, and prone to desensitization. We now compare the GH-releasing properties of GHRP-6 and a novel benzo lactam GH secretagogue L-692,585 using chronically cannulated guinea p igs and automated blood microsampling to study the effects of repeated exposure to these secretagogues. L-692,585 was approximately tenfold less potent than GHRP-6 for GH release, but it synergized strongly wit h GRF. Serial injections of GRF, GHRP-6 or L-692,585 at intervals of 6 0 or 90 min produced variable GH release which followed a cyclic patte rn of responsiveness. Prolonging the pulse interval to 3 h produced mo re regular responses to both GHRP-6 and L-692,585. Continuous i.v. inf usion of low doses of either secretagogue elicited an initial GH relea se, and amplified the spontaneous GH secretory pattern over the next 6 h. We conclude that L-692,585 and GHRP-6 share similar in vivo proper ties, and that intermittent responsiveness to frequent injections is s imilar for all three secretagogues, and is a property of the conscious animal rather than of any secretagogue type. More consistent response s can be obtained with less frequent injections that more closely matc h the endogenous GH rhythm, whereas continuous exposure to these secre tagogues leads to amplified endogenous secretion. Our results show tha t the interpretation of in vivo effects of these peptide and non-pepti de secretagogues will need to take account of their interaction with t he endogenous mechanisms governing GH release.