In order to investigate whether modulation of the effects of corticotropin-releasing hormone (CRH) by arginine vasopressin (AVP) and atrial natriuretic hormone (ANH) is sensitive to circadian fluctuations, 12 healthy male volunteers were administered 100 micrograms hCRH during 30 min infusion of placebo, 3 IU AVP, or 150 micrograms ANH, the experiment being carried out in the morning (0800h) or in the evening (1900h). Compared with placebo, AVP significantly amplified the CRH-induced adrenocorticotropin hormone (ACTH) surge both in the morning and in the evening, whereas it enhanced cortisol secretion only in the evening. In contrast, ANH significantly reduced the ACTH surge, but only in the evening, and it reduced the cortisol surge in the morning compared to the evening. During ANH infusion plasma AVP levels were suppressed both in the morning and in the evening, pointing to a hypothalamic site of action in addition to the pituitary and adrenocortical effects. The ACTH secretion profiles were indistinguishable between morning and evening in all three experimental conditions, whereas cortisol profiles differed significantly depending on the time of day in the AVP and ANH condition, but not for placebo.