EFFECTS OF CONTINUOUS AND REPETITIVE ADMINISTRATION OF A POTENT ANALOG OF GH-RH(1-30)-NH2 ON THE GH RELEASE IN RATS TREATED WITH MONOSODIUMGLUTAMATE

To assess the efficacy of a potent GH-releasing hormone (GH-RH) analog (D-Ala(2),Nle(27),Gaba(30)-GH-RH-(1-30)-amide) in the treatment of GH deficiency, we investigated the effects of chronic administration of this analog (A-495) on growth responses in monosodium glutamate (MSG)- lesioned rats, Basal serum GH concentrations, GH responses to bolus in jections of GH-RH, as well as acceleration of body gain and linear gro wth were compared after long-term continuous and repetitive administra tion of A-495. The effects of continuous and repetitive administration of the analog on GH responses in vitro were also compared using the s uperfused pituitary cell system method, Treatment with MSG reduced the body weight and linear growth of the animals (-22% and -11%, respecti vely), the basal serum GH concentration (-66%), and the GH-RH-induced absolute GH responses (-61%) but did not alter the relative GH respons es (to basal GH concentrations). Repetitive administration of 10 mu g daily doses of A-495 at 24 h intervals for 2 weeks highly increased th e GH responsiveness to GH-RH and induced catch-up growth, by which MSG -treated animals achieved the growth rate of normal controls, However, basal serum GH concentrations were only modestly enhanced. Continuous infusion of A-495 at the same daily dose resulted in slight increases in the GH-RH-induced GH rises, moderate acceleration of body gain, an d no change in linear growth, Basal serum GH concentrations were not s ignificantly influenced by this treatment. These results demonstrate t hat exogenous GH-RH pulses administered at lower frequency than the fr equency of the physiological GH secretion are able to fully restore th e normal growth rate of the GH deficient rats, The effectivity of the treatment is rather dependent on the magnitude of GH rises than the ba sal GH level. Although continuous administrations of the GH-RH is also have some effect on the body gain, repetitive administration is more effective at the same daily dose, Our results from in vitro experiment s show that, in addition to the low magnitude of the GH-RH-stimulated GH rises, desensitization of the GH secretory response might also be a ccounted for the low effectivity of the continuously administered GH-R H. Present results demonstrate the therapeutic usefulness of our new G H-RH analog and are the first to evidence that GH-RH need not be admin istered as frequently as the appearance of the endogenous GH pulses to restore the normal growth of the GH deficient rats.