Paya D, Maupoil V, Schott C, Rochette L, Stoclet J C
Laboratoire de Pharmacologie Cellulaire et Moléculaire, CNRS URA 600, Illkirch, France.
Cardiovasc Res. 1995 Dec;30(6):952-9.
Lipopolysaccharide (LPS) induces early (within 1 h) and delayed (after several hours) impairment of vascular reactivity to catecholamines whose mechanisms are different, although they probably both involve nitric oxide (NO). Temporal and quantitative relationships between hyporeactivity to noradrenaline and NO production were investigated in a rat model of endotoxaemia allowing to clearly distinguish the two phases of hyporeactivity.
Anaesthetised rats were infused with LPS (14 mg kg-1 h-1) for 1 h. Pressure responses to noradrenaline (NA) and circulating NO derivatives (nitrosyl haemoglobin, NO2-, NO3-) were monitored for 5 h after the onset of infusion. Reactivity to NA and tissue cyclic GMP level were also assessed ex vivo, in aortic rings taken at different experimental times.
LPS-induced early hyporeactivity to NA was associated with a moderate but significant increase in plasma NO3- level, without any significant change in concentration of the other circulating NO derivatives. Neither reactivity ex vivo nor cyclic GMP content were modified in aortae taken after 1 h of LPS infusion. By contrast, delayed hyporeactivity (5 h after the onset of LPS infusion) was associated with a large increase in all circulating NO derivatives (up to 2.5 fold), enhanced aortic cyclic GMP level and aortic hyporeactivity ex vivo. Pre-treatment of rats with NG-nitro-L-arginine methyl ester (1 mg kg-1 i.v.) entirely prevented early hyporeactivity and rise in NO3- concentration. In addition it attenuated in comparable proportion both delayed hyporeactivity to NA in vivo and circulating levels of NO derivatives.
The results confirm the involvement of NO in the two phases of hyporeactivity to NA induced by LPS. They strongly support the view that a circulating factor is involved in triggering endothelial NO release during the early phase, whereas the delayed phase is associated with a high production of NO in vascular smooth muscle resulting from the induction of NO synthase.
脂多糖（LPS）可诱导血管对儿茶酚胺反应性的早期（1小时内）和延迟（数小时后）损害，其机制不同，尽管可能都涉及一氧化氮（NO）。在内毒素血症大鼠模型中研究了对去甲肾上腺素反应性降低与NO产生之间的时间和定量关系，该模型能够清楚地区分反应性降低的两个阶段。
将麻醉的大鼠以14mg·kg-1·h-1的速度输注LPS 1小时。输注开始后5小时监测对去甲肾上腺素（NA）的压力反应和循环中的NO衍生物（亚硝基血红蛋白、NO2-、NO3-）。还在不同实验时间采集的主动脉环中离体评估对NA的反应性和组织环磷酸鸟苷水平。
LPS诱导的对NA的早期反应性降低与血浆NO3-水平适度但显著升高相关，其他循环NO衍生物的浓度无显著变化。LPS输注1小时后采集的主动脉中，离体反应性和环磷酸鸟苷含量均未改变。相比之下，延迟性反应性降低（LPS输注开始后5小时）与所有循环NO衍生物大幅增加（高达2.5倍）、主动脉环磷酸鸟苷水平升高和离体主动脉反应性降低相关。用NG-硝基-L-精氨酸甲酯（1mg·kg-1静脉注射）预处理大鼠可完全预防早期反应性降低和NO3-浓度升高。此外，它以相当的比例减弱了体内对NA的延迟性反应性降低和NO衍生物的循环水平。
结果证实NO参与了LPS诱导的对NA反应性降低的两个阶段。它们有力地支持了这样一种观点，即在早期阶段，一种循环因子参与触发内皮NO释放，而延迟阶段与由NO合酶诱导导致的血管平滑肌中NO的高产生有关。
