Activation of the hypothalamic-pituitary-adrenocortical axis is a major component of the body's response to stress. Current theories on the pathophysiology of disorders associated with hyperfunction of the axis, such as depression and Cushing's stress, are based on the concept that anterior pituitary adrenocorticotropin (ACTH) secretion is stimulated by hypothalamic corticotropin-releasing hormones and inhibited by adrenal corticosteroids. Hypothalamic inhibitory control of pituitary ACTH secretion has been also postulated, but has not gained general acceptance because of the lack of definitive evidence for a corticotropin-release inhibiting hormone. It is shown here that in conscious rats stress-induced secretion of ACTH and corticosterone is markedly enhanced by the immunoneutralisation of atriopeptin. Therefore, we propose that atriopeptin is a physiologically relevant corticotropin-release inhibiting hormone.
If 1 mM supplemental Ca++, or 1.6 mg hemoglobin (Hb)/ml medium (23.5 uM, a concentration comparable to that in 1 ml mouse blood), was added to Eagle's minimum essential medium (MEM) (which contains 1 mM Ca++), basal and maximally stimulated 20-dihydroprogesterone (20-DHP) secretion by cultured Y-1 mouse adrenal tumor cells [49-65th passages] could be measured by radioimmunoassay after a 0.5 hr incubation. ACTH-stimulated, but not basal, 20-DHP secretion increased after 1 mM Ca++ treatment. 5 mM EGTA significantly reduced basal and stimulated 20-DHP secretion, although significant ACTH stimulation still remained. Basal and stimulated secretion significantly increased when Hb was present. Although O2 involvement in the Hb effect was tested by bubbling medium with 100% O2 for 10 minutes, basal and stimulated secretion was unaffected. Since proteins, such as Hb, non-specifically bind free steroids, enhancing secretion, albumin (Al) was compared to Hb. Al enhanced unstimulated, but not ACTH-stimulated, 20-DHP secretion. The Hb effect may not be due to non-specific protein-steroid binding. Ca++ supplementation and chelation studies suggest the necessity to optimize co-factors in steroidogenic tissue incubation media to maximize basal and stimulated steroid synthesis and secretion. Since physiologically relevant Hb levels enhanced basal and stimulated Y-1 cell steroid secretion by mechanisms other than protein-steroid binding and soluble O2 had little effect, Hb may more efficiently transport O2 to cultured cells than soluble O2 diffusion through medium does.
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