Sevransky Jonathan, Vandivier R William, Gerstenberger Eric, Correa Rosalee, Ferantz Victor, Banks Steven M, Danner Robert L, Eichacker Peter Q, Natanson Charles
Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, USA.
Shock. 2005 Mar;23(3):281-8.
We investigated nitric oxide (NO) as a possible cause of the cardiac dysfunction associated with high, lethal doses of tumor necrosis factor-alpha (TNF-alpha) in dogs. Eighty-seven awake, 2-year-old (10-12 kg), purpose-bred beagles were randomized to receive an infusion of saline or N-monomethyl-L-arginine (L-NMMA), a nonselective NO synthase (NOS) inhibitor, as a 40 mg kg bolus followed by a 40 mg kg(-1) h(-1) infusion for 3 to 6 h 3 h before (prophylactic) or 3 h after (therapeutic) challenge with TNF-alpha (60 microg kg(-1)) or vehicle. Serial radionuclide-heart scans and thermodilution pulmonary artery catheter hemodynamic measurements were performed. The effects of prophylactic L-NMMA on TNF-alpha-induced cardiac dysfunction as measured by decreases in mean left ventricular (LV) ejection fraction and downward and rightward shifts of LV function plots (peak systolic pressure versus end systolic volume index and LV stroke work index versus end diastolic volume index) were significantly different comparing early (3-6 h) and delayed (24 h) time points (P = 0.02). Prophylactic L-NMMA therapy did not appear to fully prevent early (3-6 h) TNF-alpha-induced cardiac dysfunction, but at 24 h, complete protection was seen. Therapeutic L-NMMA did not appear to fully protect the heart from TNF-alpha-induced early or delayed cardiac dysfunction (P = NS). Similarly, L-NMMA given prophylactically, but not therapeutically, blocked TNF-alpha-induced increases in exhaled NO flow rates and plasma nitrite and nitrate concentrations (both P = 0.02). These data suggest that TNF-alpha initiates two phases of cardiac injury: an early (3-6 h) phase that may be partially NO independent and a delayed (24 h) phase that is NO dependent. The delayed, more persistent dysfunction can be completely blocked by high doses of a nonselective NOS inhibitor administered before TNF-alpha.
我们研究了一氧化氮（NO）是否可能是犬类因高致死剂量肿瘤坏死因子-α（TNF-α）导致心脏功能障碍的原因。87只清醒的、2岁（体重10 - 12千克）、专门培育的比格犬被随机分为两组，分别接受生理盐水或N-单甲基-L-精氨酸（L-NMMA，一种非选择性一氧化氮合酶（NOS）抑制剂）静脉输注，先给予40毫克/千克的推注剂量，随后以40毫克/千克⁻¹·小时⁻¹的速度输注3至6小时，在给予TNF-α（60微克/千克）或赋形剂进行攻击前3小时（预防性）或攻击后3小时（治疗性）给药。进行了系列放射性核素心脏扫描和热稀释肺动脉导管血流动力学测量。通过平均左心室（LV）射血分数降低以及LV功能图（收缩压峰值与收缩末期容积指数、LV每搏功指数与舒张末期容积指数）向下和向右偏移来衡量预防性L-NMMA对TNF-α诱导的心脏功能障碍的影响，比较早期（3 - 6小时）和延迟（24小时）时间点时差异显著（P = 0.02）。预防性L-NMMA治疗似乎并未完全预防早期（3 - 6小时）TNF-α诱导的心脏功能障碍，但在24小时时，可见完全保护作用。治疗性L-NMMA似乎并未完全保护心脏免受TNF-α诱导的早期或延迟心脏功能障碍（P =无显著性差异）。同样，预防性而非治疗性给予L-NMMA可阻断TNF-α诱导的呼出NO流速以及血浆亚硝酸盐和硝酸盐浓度升高（两者P = 0.02）。这些数据表明，TNF-α引发了两个阶段的心脏损伤：一个早期（3 - 6小时）阶段，可能部分不依赖于NO；以及一个延迟（24小时）阶段，依赖于NO。在TNF-α之前给予高剂量非选择性NOS抑制剂可完全阻断延迟出现的、更持久的功能障碍。
