Transgenic mice overexpressing the human GH-releasing
hormone (hGHRH) gene, an animal model of
acromegaly, were used to investigate the effects of potent GHRH antagonists
MZ-4-71 and
MZ-5-156 on the excessive GH and
insulin-like growth factor I (
IGF-I) secretion caused by overproduction of hGHRH. Because
metallothionein (MT)-GHRH mice express the hGHRH transgene in various tissues, including the pituitary and hypothalamus, initial experiments focused on the effectiveness of the GHRH antagonists in blocking basal and stimulated GH secretion from pituitary cells in vitro. Both
MZ-4-71 and
MZ-5-156 suppressed basal release of GH from superfused MT-GHRH pituitary cells, apparently by blocking the action of endogenously produced hGHRH. In addition, these antagonists effectively eliminated the response to stimulatory action of exogenous
hGHRH(1-29)NH2 (30 and 100 nM). To ascertain whether
MZ-4-71 and
MZ-5-156 could antagonize the effect of hGHRH hyperstimulation in vivo, each antagonist was administered to MT-GHRH transgenic mice in a single iv dose of 10-200 microg. Both compounds decreased serum GH levels in transgenic mice by 39-72% at 1 h after injection. The inhibitory effect of 50 microg
MZ-5-156 was maintained for 5 h. Twice daily ip administration of 100 microg
MZ-5-156 for 3 days suppressed the highly elevated serum GH and
IGF-I concentrations in transgenic mice by 56.8% and 39.0%, respectively. This treatment also reduced
IGF-I messenger RNA levels in the liver by 21.8% but did not affect the level of GH
messenger RNA in the pituitary. Our results demonstrate that GHRH antagonists
MZ-4-71 and
MZ-5-156 can inhibit elevated GH levels caused by overproduction of hGHRH. The suppression of circulating GH concentrations induced by the antagonists seems to be physiologically relevant, because both
IGF-I secretion and synthesis also were reduced. Our findings, showing the suppression of GH and
IGF-I secretion with GHRH antagonists, suggest that this class of analogs could be used for the diagnosis and
therapy of disorders characterized by excessive GHRH secretion.