Induction of reversible growth retardation and growth hormone deficiency by blockade of norepinephrine synthesis in the rat

Abstract

Norepinephrine is a major regulator of the release of growth hormone. Diethyldithiocarbamate, a dopamine-β-hydroxylase inhibitor, reduces norepinephrine synthesis and acutely inhibits growth hormone (GH) secretion. To investigate the long-term effects of dopamine-β-hydroxylase blockade on growth, we administered diethyldithiocarbamate (0, 40, 100 or 400 mg/kg sc b.i.d.) to 21-day-old female rats for 10 days. Food intake, body weight, and tail length were measured twice a week. Plasma GH levels and hypothalamic dopamine and norepinephrine content were measured; messenger ribonucleic acids (mRNAs) for GH-releasing hormone and somatostatin were determined by quantitative in situ hybridization. Diethyldithiocarbamate administration decreased GH levels (p<0.05) and retarded growth in a dose-dependent manner (p<0.05), without altering food intake. Co-administration of GH partially reversed the growth retardation in diethyldithiocarbamate-treated animals (p<0.05). Diethyldithiocarbamate treatment also increased the hypothalamic dopamine/norepinephrine ratio (1.13 vs 0.41 control, p<0.05). Local levels of GH-releasing hormone and somatostatin mRNA were not altered by treatment. After discontinuation of diethyldithiocarbamate, growth rates returned to normal or transiently even to supranormal values. Norepinephrine synthesis blockade with diethyldithiocarbamate provides a model for reversible growth retardation, in which GH levels are decreased in the absence of decreased GH-releasing hormone mRNA. These results support a role for norepinephrine in the regulation of normal growth.