|Budget Amount *help
¥3,100,000 (Direct Cost : ¥3,100,000)
Fiscal Year 1999 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 1998 : ¥1,700,000 (Direct Cost : ¥1,700,000)
To elucidate the regulation of GH secretionin rats, I examined the mode of action of GH releasing peptide (GHRP)/GH-secretagogue (GHS) and the regulation of pituitary GHS receptor (GHS-R) gene expression.
1. In the radioreceptor assay, ィイD1125ィエD1I-SS binding to the pituitary was inhibited by GHRP or ACTH in a dose dependent manner. Neither GHRP nor SS alone changed the intracellular cAMP content in the primary rat pituitary cell culture. Although GHRH induced cAMP increase was not influenced by GHRP, GHRP attenuated the inhibitory effect of SS on GHRH stimulated cAMP. On the other hand, addition of ACTH in the primary rat pituitary cell culture did not change the GH release, however ACTH blocked the inhibitory effect of SS on GH release. These data suggest that GHRP and ACTH, which inhibit SS binding, act as SS antagonists.
2. In the primary rat pituitary cell culture, thyroid hormone or dexamethasone dose-dependently increased the GHS-R mRNA level and GHRP decreased the GHS-R mRNA level. In vivo experiments, adrenalectomy induced a decrease in the pituitary GHS-R mRNA level, which was restored by the subcutaneous administration of dexamethasone. Food deprivation increased and continuous iv infusion of GHRP decreased the pituitary GHS-R mRNA level. These data suggest that GHS-R gene expression is up-regulated by thyroid hormone, dexamethasone and food deprivation, and down-regulated by GHRP.
3. Ghrelin, which was recently discovered as an endogenous ligand specific for GHS-R, dose-depen dently stimulated GH secretion. Combined iv administration of ghrelin and GHRH acted synergistically on GH secretion in the urethan anesthetized rats. However, the combined incubation of ghrelin and GHRH did not produce synergistic effect on GH release in the primary rat pituitary cell culture. Taken together, ghrelin stimulates GH release acting not only on the pituitary but also on the ectra-pituitary where GHS-R exists.