Nanobashvili Joseph, Neumayer Christoph, Fuegl Alexander, Punz Andreas, Blumer Roland, Mittlböck Martina, Prager Manfred, Polterauer Peter, Dobrucki Lawrence W, Huk Ihor, Malinski Tadeusz
Department of Vascuar Surgery, Ludwig Blotzmann Research Institute for Vascular Medicine, University of Vienna, Austria.
J Vasc Surg. 2004 Apr;39(4):868-77. doi: 10.1016/j.jvs.2003.10.060.
Enhanced production of superoxide in L-arginine-depleted environments and concomitant reduction of nitric oxide (NO) concentration are involved in ischemia-reperfusion (I/R) injury. Treatment with L-arginine or antioxidative vitamins alone and in combination was used to mollify I/R injury in skeletal muscle. Untreated rabbits were compared with those treated with L-arginine/antioxidative vitamin cocktail Omnibionta only, or a combination of L-arginine/ antioxidative vitamins during hind limb I/R (2.5 hours/2 hours). NO was continuously measured in vivo. Plasma malondialdehyde (MDA) served as the measure of oxygen free radical formation. Interstitial edema formation, microvessel diameter alterations, microvessel plugging, and blood flow changes were used as indicators of I/R injury. The MDA level in untreated animals 2 hours after reperfusion was significantly higher than in control animals (0.81 micromol/L +/- 0.14 micromol/L vs 0.57 micromol/L +/- 0.11 micromol/L; P<.05), indicating enhanced production of oxygen free radicals. This sequela paralleled the decreasing concentration of NO, which dropped below the detection limit (1 nmol/L) after reperfusion. Microvascular changes during I/R injury were expressed as a 40% decrease in microvessel diameter and adhesion of neutrophils in 20% of microvessels, which led to a consequent 60% reduction in blood flow, demonstrating "no reflow" (reperfusion failure after restoration of blood flow). The increase in the fraction of muscle interfiber area by 85% indicated prominent edema formation. Treatment with antioxidative vitamins alone had a minimally positive effect on edema formation and microvascular plugging, possibly by suppression of oxygen free radical production, as expressed by the reduction in plasma MDA levels. However, this therapy failed to preserve basal NO production and to protect from microvascular constriction and no reflow. Treatment with L-arginine alone had a stronger protective effect, maintaining basal NO production, further reduction of neutrophil plugging, abolition of microvascular constriction, and no reflow. The combination of antioxidative vitamins and L-arginine was the best treatment against I/R injury, expressed not only by the protection of microvessel constriction, but also by abolition of microvascular plugging, increase in NO production (68 nmol/L +/- 5 nmol/L) over the basal level (52 nmol/L +/- 7 nmol/L), and higher blood flow, as compared with treatment with L-arginine or antioxidative vitamins alone.
在精氨酸缺乏的环境中超氧化物生成增加以及一氧化氮（NO）浓度随之降低与缺血再灌注（I/R）损伤有关。单独或联合使用L-精氨酸或抗氧化维生素治疗，以减轻骨骼肌的I/R损伤。将未治疗的兔子与仅用L-精氨酸/抗氧化维生素鸡尾酒Omnibionta治疗的兔子，或在下肢I/R（2.5小时/2小时）期间联合使用L-精氨酸/抗氧化维生素治疗的兔子进行比较。在体内连续测量NO。血浆丙二醛（MDA）用作氧自由基形成的指标。间质水肿形成、微血管直径改变、微血管堵塞和血流变化用作I/R损伤的指标。再灌注2小时后，未治疗动物的MDA水平显著高于对照动物（0.81微摩尔/升±0.14微摩尔/升对0.57微摩尔/升±0.11微摩尔/升；P<0.05），表明氧自由基生成增加。这种后遗症与NO浓度降低平行，再灌注后NO浓度降至检测限（1纳摩尔/升）以下。I/R损伤期间的微血管变化表现为微血管直径减少40%，20%的微血管中有中性粒细胞黏附，导致血流随之减少60%，显示出“无复流”（血流恢复后再灌注失败）。肌肉纤维间面积分数增加85%表明形成了明显的水肿。单独使用抗氧化维生素治疗对水肿形成和微血管堵塞有最小的积极作用，可能是通过抑制氧自由基生成，如血浆MDA水平降低所示。然而，这种疗法未能维持基础NO生成，也未能防止微血管收缩和无复流。单独使用L-精氨酸治疗具有更强的保护作用，维持基础NO生成，进一步减少中性粒细胞堵塞，消除微血管收缩和无复流。抗氧化维生素和L-精氨酸联合使用是对抗I/R损伤的最佳治疗方法，不仅表现为对微血管收缩的保护，还表现为消除微血管堵塞、NO生成增加（68纳摩尔/升±5纳摩尔/升）超过基础水平（52纳摩尔/升±7纳摩尔/升）以及与单独使用L-精氨酸或抗氧化维生素治疗相比更高的血流。
