Shibata M, Parfenova H, Zuckerman S L, Leffler C W
Department of Physiology and Biophysics, University of Tennessee, Memphis 38163, USA.
Brain Res Bull. 1996;39(4):241-7. doi: 10.1016/0361-9230(95)02142-6.
The present study in piglets was designed to examine cerebrovascular effects of tumor necrosis factor-alpha (TNF alpha) and potential mechanisms involved. Anesthetized new-born pigs with closed cranial windows implanted were used. Effects of nitric oxide synthase (NOS) inhibitors, NG-nitro-L-arginine (L-NNA) and aminoguanidine, and a prostaglandin H synthase inhibitor, indomethacin, on pial arteriolar responses to TNF alpha were determined. In addition, cortical cerebrospinal fluid (CSF) prostanoids (PGE2 and 6-keto-PGF1 alpha) and cyclic nucleotides (cAMP and cGMP) were examined as indices of local cerebral production. Diameters of pial arterioles were recorded every 5 min for 30 min following topical infusion of TNF alpha under the window. CSF was sampled at the end of the 30-min recordings. TNF alpha (10(-8) and 10(-7) M) caused dilation of pial arterioles and increased CSF prostanoids and cyclic nucleotides. Indo-methacin blocked TNF alpha-induced vasodilation and the increase of prostanoids and cAMP, but not of cGMP. L-NNA and amino-guanidine blocked TNF alpha-induced vasodilation. Both inhibitors attenuated TNF alpha-induced prostanoid increase. Aminoguanidine blocked TNF alpha-induced increased cGMP and attenuated the increase in cAMP. These results are consistent with the hypothesis that TNF alpha increases cAMP via prostanoid synthesis. They also suggest that TNF alpha increases cGMP through nitric oxide synthesis, which, in addition, may promote production of prostanoids and, thus, cAMP.
本项针对仔猪的研究旨在检测肿瘤坏死因子-α（TNFα）对脑血管的影响及其潜在机制。实验采用植入了闭合式颅骨视窗的新生麻醉猪。测定了一氧化氮合酶（NOS）抑制剂NG-硝基-L-精氨酸（L-NNA）和氨基胍，以及前列腺素H合成酶抑制剂吲哚美辛对软脑膜小动脉对TNFα反应的影响。此外，还检测了皮质脑脊液（CSF）中的前列腺素（PGE2和6-酮-PGF1α）和环核苷酸（cAMP和cGMP），作为局部脑生成的指标。在视窗下局部输注TNFα后，每5分钟记录一次软脑膜小动脉直径，持续30分钟。在30分钟记录结束时采集脑脊液样本。TNFα（10^(-8)和10^(-7) M）可引起软脑膜小动脉扩张，并增加脑脊液中的前列腺素和环核苷酸。吲哚美辛可阻断TNFα诱导的血管舒张以及前列腺素和cAMP的增加，但不影响cGMP。L-NNA和氨基胍可阻断TNFα诱导的血管舒张。两种抑制剂均减弱了TNFα诱导的前列腺素增加。氨基胍可阻断TNFα诱导的cGMP增加，并减弱cAMP的增加。这些结果与TNFα通过前列腺素合成增加cAMP的假说一致。它们还表明，TNFα通过一氧化氮合成增加cGMP，此外，一氧化氮合成还可能促进前列腺素的产生，进而促进cAMP的产生。
