IN THE RAT, ENDOGENOUS NITRIC-OXIDE NODULATES THE RESPONSE OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS TO INTERLEUKIN-1-BETA, VASOPRESSIN, AND OXYTOCIN

Nitric oxide (NO) synthase (NOS), the enzyme responsible for NO format ion, is found in hypothalamic neurons containing oxytocin (OT), vasopr essin (VP), and to a lesser extent corticotropin-releasing factor (CRF ). Because NO is reported to modulate endocrine activity, we have inve stigated the hypothesis that endogenous NO participates in ACTH releas ed by various secretagogues in the rat. In the adult male rat, the int ravenous injection of interleukin-1 beta (IL-1 beta; 0.2-0.3 mu g/kg), VP (0.3-0.9 mu g/kg), and OT (30 mu g/kg) significantly increased pla sma ACTH and corticosterone levels. Pretreatment with the L-form, but not the D-form, of N(omega)nitro-L-arginine-methylester (L-NAME; a spe cific inhibitor of NOS) markedly augmented the effects of these secret agogues whether it was injected acutely or over a 4 d period. Blockade of NOS activity also caused significant (P < 0.01) extensions of the duration of action of IL-1 beta, VP, and OT. In contrast, L-NAME did n ot significantly alter the stimulatory action of peripherally injected CRF, or centrally administered IL-1 beta. Administration of L-arginin e, but not D-arginine (100 mg/kg), used as a substrate for basal NO sy nthesis and which did not by itself alter the activity of the hypothal amic-pituitary-adrenal (HPA) axis, blunted IL-1-induced ACTH secretion , and reversed the interaction between L-NAME and IL-1 beta. The stimu latory action of endotoxin, a lipopolysaccharide that releases endogen ous cytokines, was also augmented by inhibition of NO formation. The o bservation that blockade of NO formation specifically augmented the ho rmonal effect of signals released peripherally during immune stimulati on suggests that endogenous NO may restrain the stimulation of the HPA axis during conditions of increased cytokine production.