Thiemermann C, Szabó C, Mitchell J A, Vane J R
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, United Kingdom.
Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):267-71. doi: 10.1073/pnas.90.1.267.
This study investigates the role of nitric oxide (NO) and the induction of a calcium-independent NO synthase (NOS) in development of vascular hyporeactivity to norepinephrine (NE) and vascular decompensation associated with hemorrhagic shock (HS) in the anesthetized rat. HS for 120 min caused a time-dependent reduction of the pressor responses to NE. This hyporeactivity is mediated by an enhanced release of NO by the constitutive NOS, for it was reversed by NG-nitro-L-arginine methyl ester (NO2Arg), an inhibitor of both constitutive and inducible NOS, but it was not prevented by dexamethasone, an inhibitor of NOS induction. Vascular decompensation following prolonged periods of HS was characterized by a failure of control animals to maintain arterial blood pressures despite reinfusion of blood. This progressive decrease in blood pressure is mediated by enhanced formation of NO by the inducible NOS, for it was prevented by NO2Arg or dexamethasone. A strong increase in calcium-independent (inducible) NOS activity was observed in several organs after 150 and 330 min of HS, being most pronounced in lung, liver, and spleen. HS for 330, but not 150, min also caused hyporeactivity of rat aortic rings to vasoconstrictors, which was associated with induction of calcium-independent NOS activity in this tissue. Aortic hyporeactivity was prevented by dexamethasone pretreatment in vivo and reversed by NO2Arg in vitro. HS was not associated with an increase in plasma endotoxin levels, showing that endotoxin does not account for induction of NOS in this model. Thus, excessive NO formation induces vascular hyporeactivity and decompensation in HS, indicating that NOS inhibitors, particularly of the inducible NOS, may improve the therapeutic outcome of patients suffering from HS.
本研究探讨一氧化氮（NO）及钙非依赖性一氧化氮合酶（NOS）的诱导在麻醉大鼠血管对去甲肾上腺素（NE）反应性降低及与失血性休克（HS）相关的血管失代偿发展过程中的作用。120分钟的HS导致对NE的升压反应呈时间依赖性降低。这种反应性降低是由组成型NOS释放的NO增加介导的，因为它可被组成型和诱导型NOS的抑制剂NG-硝基-L-精氨酸甲酯（NO2Arg）逆转，但不能被NOS诱导抑制剂地塞米松阻止。长时间HS后的血管失代偿表现为尽管输血，但对照动物仍无法维持动脉血压。这种血压的逐渐降低是由诱导型NOS生成的NO增加介导的，因为它可被NO2Arg或地塞米松阻止。在HS 150分钟和330分钟后，在几个器官中观察到钙非依赖性（诱导型）NOS活性强烈增加，在肺、肝和脾中最为明显。330分钟而非150分钟的HS也导致大鼠主动脉环对血管收缩剂的反应性降低，这与该组织中钙非依赖性NOS活性的诱导有关。体内地塞米松预处理可预防主动脉反应性降低，体外NO2Arg可逆转该反应性降低。HS与血浆内毒素水平升高无关，表明内毒素在该模型中不能解释NOS的诱导。因此，过量的NO生成在HS中诱导血管反应性降低和失代偿，表明NOS抑制剂，特别是诱导型NOS抑制剂，可能改善HS患者的治疗效果。
