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 micrograms/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-beta-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 less than 0.005) and 5.5 +/- 0.7 vs. 2.0 +/- 0.6 ng/ml (p less than 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 less than 0.01)], and DDTC administration diminished the peak GH responses to GHRH [12 +/- 6 vs. 4 +/- 2 ng/ml (p less than 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.