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Intranasal Atrial Natriuretic Peptide Acts as Central Nervous Inhibitor of the Hypothalamo-Pituitary-Adrenal Stress System in Humans

Departments of Neuroendocrinology (B.P., B.S., C.D., J.B., H.L.F.) and Internal Medicine I (B.P., B.S., B.B., C.D., H.L.F.), University of Lübeck, D-23558 Lübeck, Germany

Address all correspondence and requests for reprints to: Boris Perras, M.D., Medizinische Klinik I, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, D-23558 Lübeck, Germany. E-mail: Perras{at}kfg.mu-luebeck.de.

Increased hypothalamo-pituitary-adrenal activity contributes to morbidity in widespread metabolic and psychiatric diseases. Inhibition of hypercortisolism represents a promising therapeutic strategy in these conditions, which currently cannot be used. Here, we tested the hypothesis that atrial natriuretic peptide (ANP) administered intranasally is a safe and feasible inhibitor of pituitary-adrenal activity at the central nervous level.

Thirty minutes after intranasal administration of ANP (1 mg) and placebo, pituitary-adrenal activity was stimulated in 18 healthy men by two tests: 1) a standard insulin-hypoglycemia test and 2) CRH combined with vasopressin (VP), respectively. ACTH, cortisol, VP, blood pressure, heart rate, and measures of fluid balance were also recorded.

Pretreatment with ANP suppressed cortisol (P < 0.01) and ACTH (P < 0.05) secretory responses to insulin-induced hypoglycemia to about half of that seen after placebo, but pituitary-adrenal activity was not suppressed by CRH/VP injection (P > 0.7). Indicators of fluid balance, cardiovascular parameters, and self-report measures were not influenced by the treatment.

Results indicate a strong inhibition of stimulated pituitary-adrenal activity after intranasal administration of ANP. The absence of an effect on CRH/VP-induced pituitary-adrenal responses suggests a direct action of the peptide on the central nervous system inhibiting stimulated hypothalamo-pituitary-adrenal activity at the hypothalamic level.

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