Modulatory role of the epinergic system in the neuroendocrine-immune system function

It is well recognized that the reciprocal interaction established between t he immune and neuroendocrine systems is crucial for the homeostatic adaptat ion of individuals during septicemia. In the present study, using an in viv o rat model, we investigated the degree of participation of central and per ipheral epinergic systems in the modulation of the hypothalamic-pituitary-a drenal and immune axes' functions during endotoxemia. For this purpose, acu te endotoxemia was induced in adult male rats pretreated intraperitoneally with either different inhibitors of phenylethanolamine-N-methyltransferase (PNMT) [which are active either peripherally (SKF 29661) or both peripheral ly and centrally (SKF 64139), thus lowering epinephrine (EPI) synthesis] or vehicle only (CTRL). Twelve hours after pretreatment, animals were intrape ritoneally injected with vehicle alone (basal) or vehicle containing bacter ial lipopolysaccharide (LPS) and sacrificed 2 h later. A significant (p < 0 .05 vs. the respective basal value) hypoglycemia was found in all groups st udied. No pretreatment modified basal plasma adrenocorticotropic hormone (A CTH), glucocorticoid and cytokine concentrations. Endotoxin-stimulated ACTH secretion was severalfold (p < 0.05) higher than the respective basal valu e in CTRL and in SKFs-pretreated rats; however, the plasma ACTH levels afte r LPS were significantly (p < 0.05 vs. CTRL and SKF-29661 values) reduced i n SKF-64139-pretreated rats. All groups studied showed an appropriate adren al response to endotoxin challenge. Although no differences were found in b asal anterior pituitary (AP) ACTH content among groups, LPS treatment signi ficantly (p < 0.05 versus the respective basal value) decreased AP ACTH in CTRL and SKF 29661 groups. No pretreatment modified the basal medial basal hypothalamus (MBH) corticotropin-releasing hormone (CRH) content. Conversel y, SKF 64139 pretreatment significantly (p < 0.05 vs. CTRL and SKF 29661 va lues) reduced basal median eminence (ME) CRH content, and LPS administratio n significantly (p < 0.05) decreased ME CRH in CTRL and SKF-29661-pretreate d rats. SKF 64139 pretreatment significantly (p < 0.05) enhanced basal MBH and ME arginine vasopressin (AVP) contents. LPS administration significantl y (p < 0.05) decreased MBH AVP in CTRL and SKF-29661-pretreated rats and di minished (p < 0.05 vs. basal values) ME AVP in all groups. The plasma tumor necrosis factor alpha (TNF alpha) concentrations were enhanced severalfold (p < 0.05 vs. basal values) after LPS treatment in CTRL rats, but not in S KFs-treated animals. In order to explore the reduced cytokine release after LPS in PNMT-inhibited rats, additional ex vivo experiments were performed by using peripheral mononuclear cells (PMNC) from both CTRL and SKF-29661-p retreated rats. The results of these experiments confirmed an immune dysfun ction after inhibition of peripheral EPI synthesis; in fact, basal and conc anavalin-A-stimulated TNF alpha secretions were significantly (p < 0.05) lo wer in SKF-29661-treated than in CTRL PMNC, while, interestingly, addition of EPI (10(-7) M) to the medium fully restored these effects. These data de monstrate that: (1) the mechanism whereby LPS-induced hypoglycemia was inde pendent of epinergic activity; (2) selective central inhibition of epinergi c function reduced endotoxin-stimulated ACTH secretion, an effect that coul d mainly be due to a decrease in CRH-ergic activity; (3) the central epiner gic system positively and negatively modulates CRH- and AVPergic functions, respectively, and (4) inhibition of peripheral PNMT activity reduced immun e system function in vivo and ex vivo. It is further suggested that low peripheral levels of EPI could be benefici al for the body's defense mechanisms during endotoxic shock. copyright (C) 2000 S. Karger AG. Basel.