Effects of acute and chronic administration of a new potent antagonist of growth hormone-releasing hormone in rats: mechanisms of action.

Antagonistic analogs of human GH-releasing hormone (hGHRH) are potential candidates for the treatment of disorders characterized by excessive GH secretion and especially for therapy of GH- and insulin-like growth factor (IGF)-dependent tumors. These analogs should be also useful for the studies on the mechanism of action of GHRH. In the present investigation, we evaluated the effects of chronic i.m. administration of a new potent GHRH antagonist (Ibu0,D-Arg2,Phe(4-Cl)6,Abu15,Nle27)hGHRH(1-28)+ ++Agm (MZ-4-71) on the growth rate, serum GH, and IGF-I concentration, GH responsiveness to exogenous GHRH, as well as the pituitary GH content and GHRH receptor concentration in young female rats. We also studied the consequences of acute, high-dose i.v. application of this antagonist on the basal GH and IGF-I levels in adult male rats. In addition, the ability of GHRH antagonist MZ-4-71 to prevent GH release induced by GHRH pulses was determined in vitro in the superfused rat pituitary cell system. Chronic treatment in vivo using twice daily i.m. injections of 20 microg MZ-4-71 for 2 weeks reduced the rate of increase in body weight by 21% and in body length of young rats by 36%, as compared with controls. GH responses to bolus injections of GHRH declined by 22%, and serum IGF-I concentrations by 15% at the end of the treatment. The total pituitary GH content, but not relative GH concentration, also decreased by 15% and GHRH receptor concentration by 48%, following chronic treatment with this antagonist. Bolus injections of high doses of MZ-4-71 (400 microg i.v.) induced a marked and protracted (6 h) inhibition of the basal serum GH concentration and a parallel inhibition of the serum IGF-I levels. The nadir of both the serum GH (62% decrease) and the IGF-I level (30% decrease) was found at 3 h after the injection. In vitro studies showed that MZ-4-71 was able to dose-dependently inhibit the GH-releasing effect of GHRH pulses. Present results demonstrate that GHRH antagonist MZ-4-71 is effective in vivo and that it can inhibit growth and secretion of GH and IGF-I in rats. Our findings also provide new information on the role of GHRH in regulating synthesis of GH and GHRH receptors. It is likely that antagonistic analogs of GHRH could find clinical application for reducing the growth of tumors dependent on GH or IGF-I.