Abstract

The GH-releasing activity of the α₂-adrenergic agonist clonidine has been extensively studied in the rat, but the mechanism(s) by which clonidine stimulates GH release remains controversial. In the present study, we examined the effects of various doses of clonidine on spontaneous pulsatile GH secretion in conscious rats, and tested the hypothesis that the GH-releasing activity of clonidine is mediated primarily by an inhibition of hypothalamic somatostatin (SRIF) release. In the first experiment, free-moving adult male rats were given either saline or various doses of clonidine i.v. (30, 50 and 125 μg/kg) at times of spontaneous peaks (1100 h) and troughs (1300 h) in the GH rhythm. Clonidine, at all doses tested, failed to stimulate GH release when administered at the time of a spontaneous peak. In contrast, injection of clonidine at trough times (when SRIF tone is high) consistently augmented plasma GH levels (mean ± s.e.m. integrated GH release; 30 μg/kg, 1843·0±484·0; 50 μg/kg, 1469·0± 490·3; 125 μg/kg, 1675·6 ± 513·4 vs 201·3 ± 100·1 ng/ml per 45 min in saline-injected controls; P<0·05 or less). No significant regression was observed between increasing doses of clonidine and GH release. In the second experiment, i.v. administration of 30 μg clonidine/kg during a GH trough period, 30 min prior to GH-releasing factor (GRF) challenge, significantly potentiated the GH response to GRF compared with rats given saline (7218·7 ±806·6 vs 4206·9 ± 1068·1 ng/ml per 30 min; P<0·05). Clonidine treatment, at all doses tested, resulted in hyperglycaemia and behavioural effects. These results showed that: (1) clonidine is not a potent GH secretagogue in the rat; (2) when administered i.v., clonidine exerts a maximal GH-releasing activity already at the dose of 30 μg/kg; and (3) clonidine-induced GH release in the rat occurs mainly through an inhibition of hypothalamic SRIF release rather than by stimulating GRF secretion.

Journal of Endocrinology (1994) 141, 259–266

It is presently thought that osteoprotegerin (OPG) is a cytokine involved in the regulation of osteoblast/osteoclast crosstalk and maintenance of bone mass. Recent studies showed that GH replacement therapy in GH-deficient patients was able to induce a significant increase of OPG in the plasma, as well as in the cortical and the trabecular bone. In order to determine whether GH could directly modulate OPG secretion, the effect of GH on human osteoblast-like cells (hOB) in primary culture was studied. After detecting the presence of the mRNA for the GH receptor (GHR) by RT-PCR, hOB were exposed to increasing concentrations of GH, from 0.1 to 25 ng/ml, for 24 h. The results showed that GH exposure was able to stimulate OPG secretion in a concentration-dependent manner. In addition, the OPG mRNA levels were increased, indicating that the hormone has a stimulatory effect on gene expression. The stimulatory effect on OPG expression and production was prevented by exposing the cells to tyrphostin AG490 (10 μM), an inhibitor of Janus kinase 2, which is one of the kinases involved in the intracellular pathway activated by the binding of GH to its receptor. Similar results were obtained when the cells were exposed to a receptor antagonist of GH, pegvisomant at 50 nM. GH exposure neither induced an increase in IGF-I expression nor secretion in hOB. These results suggest that the stimulation of OPG production induced by GH in hOB is specific and receptor mediated and further support the view that GH is able to modulate bone remodeling by directly influencing osteoblast–osteoclast crosstalk.