Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats
Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats
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DOI：
10.1160/th05-09-0637
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发表时间：
2006-05
影响因子：
6.7
通讯作者：
N. Harada;K. Okajima;H. Isobe;M. Uchiba
中科院分区：
文献类型：
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作者：
N. Harada;K. Okajima;H. Isobe;M. Uchiba
摘要 我们最近证明，肺感觉神经元的激活在通过释放大鼠降钙素基因相关肽（CGRP）来预防内毒素诱导的休克中发挥着关键作用。 CGRP 增加肺部内皮细胞产生前列环素 (PGI2)，从而通过抑制肿瘤坏死因子-α (TNF-α) 的产生来预防内毒素诱导的休克反应。由于抗凝血酶（AT）可增强感觉神经元的激活，我们假设 AT 可能通过增强大鼠肺感觉神经元的激活来减少内毒素引起的低血压。我们使用内毒素休克的大鼠模型研究了这种可能性。 AT 诱导的效应，包括降低内毒素治疗动物肺部低血压 (n=5) 和抑制 iNOS (n=4 或 5) 和 TNF-α (n=5) 的诱导，通过用辣椒西平 (CPZ) (n=4 或 5)（一种香草素受体拮抗剂）或 CGRP(8-37)（一种 CGRP 受体）预处理完全逆转 拮抗剂（n=4或5）。 AT 增强了内毒素诱导的肺组织 CGRP 水平的增加 (n=4)，但在用 CPZ 预处理的动物 (n=4) 中未观察到 AT 的这种作用。 CGRP 产生与 AT 相似的治疗效果 (n=5)，并且这种治疗效果通过吲哚美辛预处理完全消除 (n=4)。仅在存在 anandamide 的情况下，AT 才会增加培养的背根神经节神经元的 CGRP 释放（n = 5），而在存在蛋白激酶 A 抑制剂 KT5720 的情况下，没有观察到 AT 诱导的 CGRP 释放增加（n = 5）。在存在 anandamide 的情况下，AT 显着增加细胞内 cAMP 水平 (n=5)。这些结果强烈表明，AT 可能通过激活蛋白激酶 A 来增强感觉神经元的激活，从而减轻大鼠内毒素引起的低血压。
Summary We recently demonstrated that activation of the pulmonary sensory neurons plays a critical role in prevention of endotoxininduced shock by releasing calcitonin gene-related peptide (CGRP) in rats. CGRP increased the endothelial production of prostacyclin (PGI2) in the lungs, thereby preventing endotoxininduced shock response by inhibiting tumor necrosis factor-α (TNF-α) production. Since antithrombin (AT) enhances sensory neuron activation, we hypothesized that AT might reduce endotoxin-induced hypotension by enhancing the activation of pulmonary sensory neurons in rats. We examined this possibility using a rat model of endotoxin shock. AT-induced effects including reduction of hypotension (n=5) and inhibition of induction of iNOS (n=4 or 5) and TNF-α (n=5) in the lungs of endotoxin-treated animals were completely reversed by pretreatment with capsazepine (CPZ) (n=4 or 5), a vanilloid receptor antagonist, or CGRP(8–37), a CGRP receptor antagonist (n=4 or 5). AT enhanced endotoxin-induced increases in lung tissue levels of CGRP (n=4), but this effect of AT was not seen in animals pretreated with CPZ (n=4). CGRP produced therapeutic effects (n=5) similar to those induced by AT, and such therapeutic effects were completely abrogated by pretreatment with indomethacin (n=4). AT increased CGRP release from cultured dorsal root ganglion neurons only in the presence of anandamide (n=5),andAT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (n=5). AT markedly increased intracellular levels of cAMP in the presence of anandamide (n=5).These results strongly suggested that AT might reduce endotoxin-induced hypotension in rats by enhancing activation of sensory neurons via activation of protein kinase A.