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

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.

Adrenomedullin Stimulates Nitric Oxide Production from Primary Rat Hypothalamic Neurons: Roles of Calcium and Phosphatases

“…In vivo evidence suggests that ADM stimulates NO production in neurons. For example, the ADM receptor component RAMP-2 is expressed in nNOS-positive neurons (Xu and Krukoff, 2004b), and peripheral or central administration of ADM activates nNOS-positive neurons in the brain (Shan and Krukoff, 2000;Shan and Krukoff, 2001). Consistent with these findings, we now show that ADM stimulates a rapid and nNOS-mediated NO synthesis in cultured primary neurons in a receptor-dependent manner.…”

“…Increased NO production may also play a role in the regulatory effects of ADM on hypothalamic vasopressin secretion and body fluid homeostasis (Taylor et al, 2005). Supporting this suggestion, intracerebroventricular ADM administration activates nNOS-positive neurons in the magnocellular subdivision of the PVN (Shan and Krukoff, 2001), where vasopressin is produced. In addition, ADM has been shown to protect neurons from ischemia, and this effect is associated with elevated NO levels (Xia et al, 2006).…”

“…In addition to its actions in the periphery, ADM contributes extensively to the maintenance of homeostasis through central mechanisms. Thus, centrally administered ADM inhibits thirst and salt appetite (Taylor et al, 2005), suppresses food intake (Taylor et al, 1996), and regulates blood pressure, heart rate, and baroreflex sensitivity by modulating autonomic activity (Shan and Krukoff, 2001;Krukoff, 2004a,b, 2006).…”

“…For example, ADM activates NO-producing neurons in the hypothalamic paraventricular nucleus (PVN) and stimulates NO production in the hypothalamus (Shan and Krukoff, 2001). In addition, the hypotensive effects induced by microinjections of ADM into the PVN are attenuated by inhibition of NO synthesis (Xu and Krukoff, 2004b).…”

Decrease in arterial pressure induced by adrenomedullin in the hypothalamic paraventricular nucleus is mediated by nitric oxide and GABA

“…For instance, intracerebroventricular (i.c.v.) ADM and microinjection of ADM into the area postrema (AP) increase arterial pressure by stimulating sympathetic outflow from the brain [16][17][18][19][20][21]. Interestingly microinjection of ADM into the PVN leads to a rapid decrease in arterial pressure [22], but the mechanisms for this effect are unknown.…”