ENDOTOXIN STIMULATES AN ENDOGENOUS PATHWAY REGULATING CORTICOTROPIN-RELEASING HORMONE AND VASOPRESSIN RELEASE INVOLVING THE GENERATION OF NITRIC-OXIDE AND CARBON-MONOXIDE

Although the administration of endotoxin in vivo activates the neuroen docrine stress axis in the process of crosstalk between the immune and endocrine axes, the direct application of endotoxin to the hypothalam us in vitro does not stimulate the release of the hypothalamic peptide s controlling the hypothalamo-pituitary-adrenal (HPA) axis, corticotro pin-releasing hormone (CRH) and vasopressin. The hypothesis has theref ore been tested that endotoxin may also activate inhibitory pathways, specifically those involving the generation of nitric oxide (NO) and c arbon monoxide (CO). Studies were performed on the isolated rat hypoth alamus using endotoxin in the presence or absence of inhibitors of hem e oxygenase (which generates CO) and nitric oxide synthase, and ferrou s hemoglobin. Endotoxin alone decreased both CRH and vasopressin secre tion from the hypothalamus. However, when applied together with a nitr ic oxide synthase inhibitor, the inhibitory effect on CRH was lost. Co nversely, co-administration with heme oxygenase inhibitors transformed the inhibition of vasopressin to stimulation, while having no effect on the inhibition of CRH. Ferrous hemoglobin reversed the inhibition o f vasopressin, but did not lead to stimulation. It is therefore conclu ded that endotoxin may stimulate endogenous pathways that lead to the generation of NO, which in turn inhibits CRH. In addition, it generate s CO, which modulates the release of vasopressin. These gases are thus potential counter-regulatory controls to the activation of the HPA. ( C) 1998 Elsevier Science B.V. All rights reserved.