Sheh Yen-Ling, Hsu Chin, Chan Samuel H H, Chan Julie Y H
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, Republic of China.
Free Radic Biol Med. 2007 May 15;42(10):1610-23. doi: 10.1016/j.freeradbiomed.2007.02.019. Epub 2007 Feb 28.
We evaluated the contribution of superoxide anion (O2*-) generated by NADPH oxidase or mitochondria in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for arterial pressure maintenance are located, on cardiovascular depression induced by inducible nitric oxide synthase-derived NO after Escherichia coli lipopolysaccharide (LPS) treatment. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection of LPS bilaterally into the RVLM induced progressive hypotension, bradycardia, and reduction in sympathetic vasomotor outflow over our 240-min observation period. This was accompanied by an increase in O2*- production (60-240 min) in the RVLM, alongside phosphorylation of p47(phox) or p67(phox), upregulation of gp91(phox) or p47(phox) protein, and increase in Rac-1 or NADPH oxidase activity (60-120 min), and a depression of mitochondrial respiratory enzyme activity (120-240 min). Whereas inhibition of NADPH oxidase or knockdown of the gp91(phox) or p47(phox) gene blunted the early phase (60-150 min), coenzyme Q10 or mitochondrial K(ATP) channel inhibitor antagonized the delayed phase (120-240 min) of LPS-induced increase in O2*- production in RVLM and cardiovascular depression. We conclude that, whereas NADPH oxidase-derived O2*- in RVLM participates predominantly in the early phase, O2*- generated by depression in mitochondrial respiratory enzyme activity or opening of mitoK(ATP) channels mediates the delayed phase of LPS-induced cardiovascular depression.
我们评估了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶或线粒体产生的超氧阴离子（O2*-）在延髓头端腹外侧区（RVLM）中的作用，RVLM是维持动脉血压的交感神经运动前神经元所在的区域，该作用涉及大肠杆菌脂多糖（LPS）处理后诱导型一氧化氮合酶衍生的一氧化氮（NO）所引起的心血管抑制。在丙泊酚麻醉下的Sprague-Dawley大鼠中，双侧向RVLM微量注射LPS在我们240分钟的观察期内诱导了渐进性低血压、心动过缓以及交感缩血管神经传出活动减少。这伴随着RVLM中O2*-产生增加（60 - 240分钟），同时p47（phox）或p67（phox）磷酸化、gp91（phox）或p47（phox）蛋白上调以及Rac-1或NADPH氧化酶活性增加（60 - 120分钟），并且线粒体呼吸酶活性降低（120 - 240分钟）。虽然抑制NADPH氧化酶或敲低gp91（phox）或p47（phox）基因可减弱早期阶段（60 - 150分钟），但辅酶Q10或线粒体ATP敏感性钾（KATP）通道抑制剂可拮抗LPS诱导的RVLM中O2*-产生增加和心血管抑制的延迟阶段（120 - 240分钟）。我们得出结论，虽然RVLM中NADPH氧化酶衍生的O2*-主要参与早期阶段，但线粒体呼吸酶活性降低或线粒体KATP通道开放产生的O2*-介导了LPS诱导的心血管抑制的延迟阶段。
