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Developmental Endocrinology Branch, National Institute of Child Health and Human Development (S.R.B., E.L.W., D.J.T., S.J.R., G.P.C.); Medicinal Chemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases (D.B.L., K.C.R.); and Department of Pathology, National Cancer Institute (N.M., M.T.), National Institutes of Health, Bethesda, Maryland 20892; and the Department of Internal Medicine III, University of Leipzig (S.R.B.), Leipzig 04103; and the Institute of Pharmacology and Toxicology, Technical University of Aachen (M.J., H.G.J.), Aachen, Germany
Address all correspondence and requests for reprints to: Stefan R. Bornstein, M.D., Clinical Center, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, Bethesda, Maryland 20892.
CRH, the principal regulator of the hypothalamic-pituitary-adrenal axis and modulator of autonomic nervous system activity, also participates in the regulation of appetite and energy expenditure. Antalarmin, a pyrrolopyrimidine compound, antagonizes CRH type 1 receptor-mediated effects of CRH, including pituitary ACTH release, stress behaviors, and acute inflammation. We administered antalarmin chronically to evaluate its effects on hypothalamic-pituitary-adrenal axis function and metabolic status. Adult male rats were treated twice daily with 20 mg/kg of ip antalarmin or placebo over 11 days. The animals were weighed; plasma ACTH, corticosterone, leptin, and blood glucose levels were determined; and morphometric analyses were performed to determine adrenal size and structure, including sizing, histochemistry, immunohistochemistry, and electron microscopy. Leptin messenger RNA expression in peripheral fat was analyzed by Northern blot. Antalarmin decreased plasma ACTH (mean ± SD, 2.62 ± 0.063 pg/ml) and corticosterone concentrations (10.21 ± 1.80 µg/dl) compared with those in vehicle-treated rats [respectively, 5.3 ± 2.0 (P < 0.05) and 57.02 ± 8.86 (P < 0.01)]. Antalarmin had no significant effect on body weight, plasma leptin, or blood glucose concentrations or fat cell leptin messenger RNA levels. The width of the adrenal cortex of animals treated with antalarmin was reduced by 31% compared with that in controls without atrophy of the gland. On the ultrastructural level, adrenocortical cells were in a hypofunctional state characterized by reduced vascularization, increased content of lipid droplets, and tubulovesicular mitochondria with fewer inner membranes. The apoptotic rate was increased in the outer zona fasciculata of animals treated with the antagonist (26.6 ± 3.58%) compared with that in placebo-treated controls (6.8 ± 0.91%).
We conclude that chronic administration of antalarmin does not affect body weight, carbohydrate metabolism, or leptin expression, whereas it reduces adrenocortical function mildly, without anatomical, clinical, or biochemical evidence of causing adrenal atrophy. These results are promising for future uses of such an antagonist in the clinic.
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