Intracerebroventricular Adrenomedullin Stimulates the Hypothalamic‐Pituitary‐Adrenal Axis, the Sympathetic Nervous System and Production of Hypothalamic Nitric Oxide

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Abstract
We tested the hypothesis that central adrenomedullin stimulates activity of the hypothalamic‐pituitary‐adrenal (HPA) axis and sympathetic output from the brain, and we assessed the effects of central adrenomedullin on the nitric oxide (NO) system in the brain. In conscious rats, intracerebroventricular (i.c.v.) injections of adrenomedullin (2 nmol/kg) increased arterial pressure and heart rate, with return to baseline values within 20 min and 65 min of injections, respectively. Adrenomedullin injections augmented expression of tyrosine hydroxylase mRNA in the locus coeruleus after 4 h. Plasma concentrations of adrenocorticotropic hormone, measured with radioimmunoassay, were also increased by adrenomedullin. i.c.v. Adrenomedullin stimulated Fos expression in neurones within autonomic centres including the paraventricular nucleus (PVN) of the hypothalamus, arcuate nucleus, locus coeruleus, nucleus of the tractus solitarius and area postrema. In the PVN, large proportions of corticotropin releasing factor‐ and NO‐producing neurones were activated (Fos positive). NO production, measured with nitrate/nitrite assays, was elevated in the hypothalamus, but not brainstem, of adrenomedullin‐treated rats compared to controls. We conclude that centrally administered adrenomedullin stimulates activity of the HPA axis, the sympathetic nervous system, and the hypothalamic NO system.