Comparison Between the Influence of the Intravenous and Intracerebroventricular Injection of a Nitric Oxide Donor on Adrenocorticotropic Hormone Release and Hypothalamic Neuronal Activity

We investigated the ability of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) to release adrenocorticotropic hormone (ACTH) and up-regulate hypothalamic neurones following its intravenous (i.v.) injection. i.v. SIN-1 (0.2-1.8 mg/kg) produced dose-related increases in plasma ACTH levels which were blocked by prior neutralization of endogenous corticotropin-releasing factor (CRF) but not by vasopressin antibodies. In contrast, the intracerebroventricular (i.c.v.) injection of 50-microg SIN-1 released significantly larger amounts of ACTH, a response blunted by either CRF or vasopressin antibodies. While i.c.v. SIN-1 markedly up-regulated transcripts of the immediate early gene NGFI-B in the paraventricular nucleus (PVN) of the hypothalamus, no such response was observed following the i.v. injection of up to 2.0 mg/kg SIN-1. Finally, we found no evidence that the influence of the peripheral administration of SIN-1 on ACTH secretion is mediated by altered pituitary responsiveness to CRF or vasopressin. The fact that NO has a profound hypotensive influence in the periphery suggests that it may have released ACTH through this mechanism, although the absence of PVN neuronal response in regions that are activated by decreased blood pressure casts some doubt on this hypothesis. As the systemic injection of arginine derivatives that block NOS activity potently augment the ACTH response to circulating pro-inflammatory cytokines or vasopressin, the present findings indicate that the mechanisms responsible for this phenomenon are distinct from those responsible for ACTH released by i.v. SIN-1.