Skeletal growth acceleration with growth hormone secretagogues in transgenic growth retarded rats: pattern-dependent effects and mechanisms of desensitization.

摘要

The transgenic growth retarded (Tgr) rat is the first genetic model of growth hormone (GH) deficiency whose growth can be accelerated with exogenous GH secretagogues (GHSs). In this study, we have demonstrated that GHS-receptor (GHS-R) mRNA expression in the arcuate nucleus of Tgr rats was not significantly different to that in wild-type littermates. We have confirmed that GHS-induced elevation in body weight gain was accompanied by acceleration of skeletal growth, and that the effects of the GHS, GHRP-6, were both dose- and pattern-dependent. The growth response with continuous infusion of GHRP-6 was transient, accompanied by suppression of GH and corticosterone responses to bolus injection of GHRP-6. This desensitization occurred without downregulation of arcuate GHS-R mRNA expression, but was accompanied by elevated periventricular somatostatin mRNA expression. In contrast, pulsatile (3-hourly) infusion of GHRP-6 produced sustained growth and GH responses, which were accompanied by suppression of corticosterone responses and elevated arcuate GH-releasing factor (GRF) mRNA expression. Skeletal growth was further accelerated by coinfusion of GRF, but significant depletion of pituitary GH stores suggested that this growth rate may not be sustainable. These experiments confirm the importance of the Tgr rat for investigating the growth promoting potential of the GHSs in the context of GH-deficient dwarfism, and suggest that elevated somatostatin expression may mediate the suppression of the GRF-GH and hypothalamo-pituitary-adrenal axes following continuous GHRP-6 treatment.