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Endotoxin Stimulates Nitric Oxide Production in the Paraventricular Nucleus of the Hypothalamus through Nitric Oxide Synthase I: Correlation with Hypothalamic-Pituitary-Adrenal Axis Activation¹

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute (S.L., C.R.), La Jolla, California 92037

Address all correspondence and requests for reprints to: Catherine Rivier, Ph.D., The Salk Institute, The Clayton Foundation Laboratories for Peptide Biology, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: crivier{at}salk.edu

Nitric oxide (NO) is an unstable gas that is produced in brain tissues involved in the control of the activity of the hypothalamus-pituitary-adrenal (HPA) axis. Transcripts for constitutive neuronal NO synthase (NOS I), one of the enzymes responsible for NO formation in the brain, is up-regulated by systemic endotoxin [lipopolysaccharide (LPS)] injection. However, this change is delayed compared with LPS induced-ACTH release, which makes it difficult to determine whether it is functionally important for the hormonal response. To obtain a more resolutive time course of the NO response, we first measured NO in microdialysates of the paraventricular (PVN) nucleus of the hypothalamus. The iv injection of 100 µg/kg LPS induced a rapid and short-lived increase in concentrations of this gas, which corresponded to the initiation of the ACTH response. LPS-induced Ca²⁺-dependent NOS activity in the PVN as well as the number of PVN cells expressing citrulline (a compound produced stoichiometrically with NO) also increased significantly over a time course that corresponded to ACTH and corticosterone release. Finally, blockade of NO production with the arginine derivative N-nitro-L-arginine-methylester (L-NAME; 50 mg/kg, sc), which attenuated the ACTH response to LPS, virtually abolished basal NOS activity in the PVN, as well as anterior and neurointermediate lobes of the pituitary, and prevented the appearance of citrulline in the PVN of rats injected with LPS.

Collectively, these results show that LPS-induced activation of the HPA axis correlates with the activation of the PVN NOergic system, and supports a stimulatory role for NO in the modulation of the HPA axis in response to immune challenges.

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