CHRONIC ADMINISTRATION OF A NEW POTENT AGONIST OF GROWTH HORMONE-RELEASING HORMONE INDUCES COMPENSATORY LINEAR GROWTH IN GROWTH HORMONE-DEFICIENT RATS - MECHANISM OF ACTION

To assess the efficacy of a potent agonist analog of GH-releasing horm one (GH-RH), u(15),Nle(27),Asp(28),Agm(29)]hGH-RH(1-29)(JI-38), we inv estigated the effects of its chronic administration on growth response s in monosodium glutamate (MSG)-lesioned and normal young rats. Body w eight (BW), body length (BL), tibia length (TIL), and tail length (TAL ) were monitored. Basal serum GH concentrations, GH responses to bolus injections of GH-RH, pituitary GH and serum IGF-I concentrations were measured by RIA. Pituitary GH-RH receptor concentration and binding a ffinity was also evaluated after the treatment. Neonatal treatment wit h MSG resulted, as expected, in blunted growth and a decrease in serum and pituitary GH concentration and serum IGF-I levels. A reduction in GH-RH receptor concentration, associated with increased binding affin ity of the GH-RH receptor was also found. Chronic administration of GH -RH agonist JI-38 in doses of 2 mu g at 12-hour intervals for 2 weeks markedly increased the GH responsiveness to GH-RH and stimulated growt h, with MSG-treated animals achieving the growth rate of normal contro ls. Acceleration of growth was associated with stimulated GH synthesis and IGF-I secretion, although basal serum GH levels did not change. P ituitary GH-RH receptor concentration and binding affinity were not si gnificantly modified by the treatment. Treatment of normal young growi ng rats with agonist JI-38 did not further increase the normal growth acceleration in these rats, but stimulated the GH synthesis and augmen ted the GH secretory responsiveness. The treatment of MSG-lesioned rat s with GH-RH agonist was generally more effective in female than in ma le animals, and in some cases masked the sex differences in growth rat e. Our findings provide the first evidence that the blunted growth rat e of the MSG-lesioned rats is associated with a decreased pituitary GH -RH receptor concentration. Our work demonstrates that administration of GH-RH agonist JI-38 is able to restore the normal growth rate of th e GH-deficient rats by stimulating GH synthesis and IGF-I secretion.