In the rat, endogenous nitric oxide modulates 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 formation, is found in hypothalamic neurons containing oxytocin (OT), vasopressin (VP), and to a lesser extent corticotropin-releasing factor (CRF). Because NO is reported to modulate endocrine activity, we have investigated the hypothesis that endogenous NO participates in ACTH released by various secretagogues in the rat. In the adult male rat, the intravenous injection of interleukin-1 beta (IL-1 beta; 0.2-0.3 micrograms/kg), VP (0.3-0.9 micrograms/kg), and OT (30 micrograms/kg) significantly increased plasma ACTH and corticosterone levels. Pretreatment with the L-form, but not the D-form, of N omega nitro-L-arginine-methylester (L-NAME; a specific inhibitor of NOS) markedly augmented the effects of these secretagogues 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 not significantly alter the stimulatory action of peripherally injected CRF, or centrally administered IL-1 beta. Administration of L-arginine, but not D-arginine (100 mg/kg), used as a substrate for basal NO synthesis and which did not by itself alter the activity of the hypothalamic-pituitary-adrenal (HPA) axis, blunted IL-1-induced ACTH secretion, and reversed the interaction between L-NAME and IL-1 beta. The stimulatory action of endotoxin, a lipopolysaccharide that releases endogenous cytokines, was also augmented by inhibition of NO formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Rivier
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Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037.
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D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D010121:Oxytocin / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013237:Stereoisomerism; D013997:Time Factors; D014667:Vasopressins / Q000494:pharmacology*
D007375:Interleukin-1; D011994:Recombinant Proteins; D014667:Vasopressins; D009569:Nitric Oxide; D010121:Oxytocin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester; D003345:Corticosterone