Blockade of nitric oxide formation augments adrenocorticotropin released by blood-borne interleukin-1 beta: role of vasopressin, prostaglandins, and alpha 1-adrenergic receptors.
Blockade of nitric oxide (NO) formation with the arginine derivative L-N omega nitro-L-arginine-methylester (L-NAME) produces a dramatic increase in ACTH released by the iv injection of interleukin-1 beta (IL-1 beta). The present work investigated the potential role of three mechanisms in this effect: the activation of adrenergic receptors and/or the release of vasopressin (VP) or prostaglandins (PG). As previously observed, blockade of adrenergic receptors with prazosin and propranolol did not alter the stimulatory effect of IL-1 beta. We show here that this treatment did not significantly interfere with the potentiating influence of L-NAME 30 min after IL-1 injection, but blunted this effect at 60 min. Immunoneutralization of endogenous VP did not consistently decrease the ACTH response to IL-1 beta regardless of whether NO was present. Finally, as expected, blockade of PG synthesis with ibuprofen totally abolished IL-1 beta-induced ACTH secretion; in addition, it prevented the interaction between L-NAME and the pituitary response. In contrast to results obtained after the injection of IL-1 beta, neither the adrenergic antagonists nor ibuprofen significantly altered the ability of L-NAME to potentiate the stimulatory effect of VP. Collectively, these results indicate that the influence of NO on ACTH released by blood-borne IL-1 beta (an effect thought to be primarily exerted on nerve terminals in the median eminence) is not primarily mediated by endogenous VP. The inability of L-NAME to augment the stimulatory effect of the cytokine on ACTH secretion in the presence of ibuprofen suggests that PG play an obligatory role in the response of the hypothalamic-pituitary axis to systemic cytokine administration that cannot be compensated for by removing the restraining influence of NO. Finally, removal of the inhibitory effect of NO either unmasks the participation of adrenergic receptors in modulating the response of the hypothalamic-pituitary axis to IL-1 beta or stimulates catecholamine secretion, which, in turn, acts on CRF nerve terminals and/or synergizes with IL-1 beta-induced CRF release.
Rivier
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Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037, USA.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D007052:Ibuprofen / Q000494:pharmacology; D007375:Interleukin-1 / Q000097:blood*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D014667:Vasopressins / Q000502:physiology*
D000317:Adrenergic alpha-Antagonists; D007375:Interleukin-1; D011453:Prostaglandins; D011942:Receptors, Adrenergic, alpha; D014667:Vasopressins; D009569:Nitric Oxide; D000324:Adrenocorticotropic Hormone; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester; D007052:Ibuprofen