Yamada Takehiro, Fujino Takayuki, Yuhki Koh-ichi, Hara Akiyoshi, Karibe Hideji, Takahata Osamu, Okada Yuji, Xiao Chun-Yang, Takayama Koji, Kuriyama Shuhko, Taniguchi Takanobu, Shiokoshi Takahiro, Ohsaki Yoshinobu, Kikuchi Kenjiro, Narumiya Shuh, Ushikubi Fumitaka
Department of Pharmacology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan.
Circulation. 2003 Nov 11;108(19):2381-6. doi: 10.1161/01.CIR.0000093194.21109.EC. Epub 2003 Oct 13.
Circulatory failure in sepsis arises from vascular hyporesponsiveness, in which nitric oxide (NO) derived from inducible NO synthase (iNOS) plays a major role. Details of the cross talk between thromboxane (TX) A2 and the iNOS-NO system, however, remain unknown. We intended to clarify the role of TXA2, via the cross talk, in vascular hyporesponsiveness.
We examined cytokine-induced iNOS expression and NO production in cultured vascular smooth muscle cells (VSMCs) and cytokine-induced hyporesponsiveness of the aorta from mice lacking the TXA2 receptor (TP-/- mice). The cytokine-induced iNOS expression and NO production observed in wild-type VSMCs were significantly augmented in TP-/- VSMCs, indicating an inhibitory effect of endogenous TXA2 on iNOS expression. Furthermore, in indomethacin-treated wild-type VSMCs, U-46619, a TP agonist, inhibited cytokine-induced iNOS expression and NO production in a concentration-dependent manner, effects absent from TP-/- VSMCs. In an ex vivo system, the cytokine-induced hyporesponsiveness of aortas to phenylephrine was significantly augmented in TP-/- aorta but was almost completely canceled by aminoguanidine, an iNOS inhibitor. Accordingly, cytokine-induced NO production was significantly higher in TP-/- aorta than in wild-type aorta. Moreover, U-46619 significantly suppressed lipopolysaccharide-induced NO production in vivo only in wild-type mice.
These results suggest that TXA2 has a protective role against the development of vascular hyporesponsiveness via its inhibitory action on the iNOS-NO system under pathological conditions such as sepsis.
脓毒症中的循环衰竭源于血管反应性降低，其中诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）起主要作用。然而，血栓素（TX）A2与iNOS-NO系统之间的相互作用细节仍不清楚。我们旨在通过这种相互作用阐明TXA2在血管反应性降低中的作用。
我们检测了细胞因子诱导的培养血管平滑肌细胞（VSMC）中iNOS的表达和NO的产生，以及细胞因子诱导的缺乏TXA2受体的小鼠（TP-/-小鼠）主动脉的反应性降低情况。在野生型VSMC中观察到的细胞因子诱导的iNOS表达和NO产生在TP-/- VSMC中显著增强，表明内源性TXA2对iNOS表达有抑制作用。此外，在吲哚美辛处理的野生型VSMC中，TP激动剂U-46619以浓度依赖的方式抑制细胞因子诱导的iNOS表达和NO产生，而TP-/- VSMC中没有这种作用。在体外系统中，细胞因子诱导的主动脉对去氧肾上腺素的反应性降低在TP-/-主动脉中显著增强，但几乎完全被iNOS抑制剂氨基胍消除。因此，细胞因子诱导的NO产生在TP-/-主动脉中显著高于野生型主动脉。此外，U-46619仅在野生型小鼠体内显著抑制脂多糖诱导的NO产生。
这些结果表明，在脓毒症等病理条件下，TXA2通过对iNOS-NO系统的抑制作用，对血管反应性降低的发展具有保护作用。
