Rivier C
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037, USA.
Endocrinology. 1995 Aug;136(8):3597-603. doi: 10.1210/endo.136.8.7628398.
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.
用精氨酸衍生物L-Nω-硝基-L-精氨酸甲酯（L-NAME）阻断一氧化氮（NO）生成，会使静脉注射白细胞介素-1β（IL-1β）后促肾上腺皮质激素（ACTH）的释放显著增加。本研究探讨了三种机制在该效应中的潜在作用：肾上腺素能受体的激活和/或血管加压素（VP）或前列腺素（PG）的释放。如先前观察到的，用哌唑嗪和普萘洛尔阻断肾上腺素能受体并不会改变IL-1β的刺激作用。我们在此表明，这种处理在IL-1注射30分钟后不会显著干扰L-NAME的增强作用，但在60分钟时会减弱这种作用。无论是否存在NO，内源性VP的免疫中和都不会持续降低ACTH对IL-1β的反应。最后，正如预期的那样，用布洛芬阻断PG合成完全消除了IL-1β诱导的ACTH分泌；此外，它还阻止了L-NAME与垂体反应之间的相互作用。与注射IL-1β后获得的结果相反，肾上腺素能拮抗剂和布洛芬均未显著改变L-NAME增强VP刺激作用的能力。总体而言，这些结果表明，NO对血源性IL-1β释放的ACTH的影响（一种被认为主要作用于正中隆起神经末梢的效应）并非主要由内源性VP介导。在存在布洛芬的情况下，L-NAME无法增强细胞因子对ACTH分泌的刺激作用，这表明PG在下丘脑-垂体轴对全身细胞因子给药的反应中起必不可少的作用，而这种作用无法通过消除NO的抑制作用来补偿。最后，消除NO的抑制作用要么揭示了肾上腺素能受体在调节下丘脑-垂体轴对IL-1β反应中的参与，要么刺激了儿茶酚胺分泌，而儿茶酚胺又作用于促肾上腺皮质激素释放因子（CRF）神经末梢和/或与IL-1β诱导的CRF释放协同作用。
