Effects of Inhibition of Norepinephrine Synthesis on Spontaneous and Growth Hormone-Releasing Hormone-Induced GH Secretion in Cynomolgus Macaques: Evidence for Increased Hypothalamic Somatostatin Tone

Abstract

To define the role of noradrenergic regulation of growth hormone (GH) secretion in a primate species, spontaneous and GH-releasing hormone (GHRH) stimulated GH secretion was studied in 6 chronically catheterized adult male cynomolgus monkeys before and after inhibition of norepinephrine synthesis. Blood samples were obtained at 15-min intervals during an 8-hour period to characterize the pattern of GH secretion, and the GH response to GHRH, 10 µg/kg i.v., was determined. These measurements were repeated 2 weeks later, 2 h after the intravenous administration of 12.5 mg/kg of the dopamine-β-hydroxylase inhibitor diethyldithiocarbamate (DDTC), which has been shown to be an effective norepinephrine synthesis inhibitor in the rat. Spontaneous and stimulated GH secretory patterns before and after DDTC administration were compared. Both the frequency and the amplitude of spontaneous GH pulses were markedly reduced by DDTC [3.8 ± 0.4 before vs. 1.8 ± 0.4 peaks/8 h after DDTC (p < 0.005) and 5.5 ± 0.7 vs. 2.0 ± 0.6 ng/ml (p < 0.01)]. Areas under the curve were also reduced by DDTC treatment [10.8 ± 1.0 vs. 5.7 ± 1.1 ng · h/ml (p < 0.01)], and DDTC administration diminished the peak GH responses to GHRH [12 ± 6 vs. 4 ± 2 ng/ml (p < 0.05)]. These results are consistent with the belief that DDTC is a potent inhibitor of spontaneous and GHRH-induced GH secretion. The action of DDTC could be mediated by a reduction in GHRH due to reduced norepinephrine synthesis, by an increase in somatostatin release through a dopaminergic stimulus, or by a direct dopaminergic effect on somatotrophs.

Clonidine Potentiates the Growth Hormone (GH) Response to GH-Releasing Hormone in Norepinephrine Synthesis-Inhibited Rats: Evidence for an Alpha-2-Adrenergic Control of Hypothalamic Release of Somatostatin

“…The fact that, in DDTC rats, CLO + GRF-induced GH secretion was lower than when they were chal lenged with GRF in the presence of anti-SS serum sup ports such a possibility. On the other hand, it is also unlikely that an increased SS tone due to DDTCincreased central dopaminergic activity [11,12] could have counteracted the effect of CLO-induced GHRH se cretion on GH release. The enhanced GH response to CLO + GRF seen in DDTC rats seems to exclude such a possibility.…”

“…Our experimental approach was similar to those previously designed by McCormick et al [11] and Malozowski et al [12] in rats and monkeys, respectively. We hypothesized that the lack of « 2-adrenergic inputs to SS neurons would produce increased SS release that, in turn, would be responsible for the blockade of GH re sponses to GRF [13], To test such a possibility, the GH response to GRF in the presence of anti-SS serum was first examined in rats treated with a dopamine-p-hydroxylase inhibitor or placebo (P).…”

“…We hypothesized that the lack of « 2-adrenergic inputs to SS neurons would produce increased SS release that, in turn, would be responsible for the blockade of GH re sponses to GRF [13], To test such a possibility, the GH response to GRF in the presence of anti-SS serum was first examined in rats treated with a dopamine-p-hydroxylase inhibitor or placebo (P). Following this, we investi gated whether or not the administration of CLO was able to normalize the blunted GH secretion seen in the above studies [11,12], Therefore, the GH response to the com bined administration of GRF and CLO in adult male rats in which norepinephrine (NE) synthesis had been blocked with diethyldithio-carbamate (DDTC) allowed us to indirectly evaluate [13] the effect of CLO on the hy pothalamic SS release.…”