Endotoxin stimulates nitric oxide production in the paraventricular nucleus of the hypothalamus through nitric oxide synthase I: Correlation with hypothalamic-pituitary-adrenal axis activations

Nitric oxide (NO) is an unstable gas that is produced in brain tissues invo lved in the control of the activity of the hypothalamus-pituitary-adrenal ( HPA) axis. Transcripts for constitutive neuronal NO synthase (NOS I), one o f the enzymes responsible for NO formation in the brain, is up-regulated by systemic endotoxin [lipopolysaccharide (LPS)] injection. However, this cha nge is delayed compared with LPS induced-ACTH release, which makes it diffi cult to determine whether it is functionally important for the hormonal res ponse. 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 mu g/kg LPS induced a rapid and shor t-lived increase in concentrations of this gas, which corresponded to the i nitiation of the ACTH response. LPS-induced Ca2+-dependent NOS activity in the PVN as well as the number of PVN cells expressing citrulline (a compoun d 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-omega-nitro-L-argi nine-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 ante rior and neurointermediate lobes of the pituitary, and prevented the appear ance of citrulline in the PVN of rats injected with LPS. Collectively, these results show that LPS-induced activation of the HPA axi s 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 im mune challenges.