Effect of Nitric Oxide Synthase Inhibitors in Vivo Tumor Necrosis Factor-induced

目前的调查是为了 确定，在体内，如果一氧化氮负责 苦参碱引起的心肌抑制。基于体外 数据，我们认为细胞因子对细胞的负离子效应， 心脏由一氧化氮介导。在离体仓鼠心脏 在乳头肌中，细胞因子的这种负离子效应可以是 被N-G单甲基-L-精氨酸（NMA）（一种一氧化氮）阻断 合成酶抑制剂因为体外数据表明， 一氧化氮合酶抑制剂阻止肿瘤坏死因子 （TNF）诱导的心肌抑制快速发作和逆转， 我们研究了低剂量的重组人TNF攻击， 犬齿这种TNF激发产生显著的，早期的， 短暂心肌抑制（24小时后消退）。令人惊讶的是， 我们发现NMA不能阻止早期（最多6小时） TNF对心脏功能的有害影响。事实上，在此期间， 期间，TNF和NMA对所有心脏和血流动力学的影响 参数是相加的（即，NMA不阻断TNF作用）。 但TNF灌注后24 h，NMA可改善上述作用 TNF对某些参数的影响，如酸碱紊乱， 平均动脉压和全身血管阻力降低。 这些数据表明，TNF诱导的心脏和 血管异常可能与一氧化氮无关 生产然而，TNF的一些后期效应可能是 与一氧化氮的产生有关。鉴于这一发现 提示TNF输注后24小时NMA的有益作用， 我们评估了一氧化氮抑制在以下情况下的作用： 更高剂量的TNF导致更长时间的心肌抑制。 先前在犬中使用TNF激发的实验表明， 这是一个合理的假设，（即，可能有两个阶段 心脏损伤）。在犬科动物中，有一个早期（小于8小时）， 心肌抑制的剂量非依赖性机制和迟发性 （超过24小时）心肌剂量依赖性机制 萧条据推测，抑制一氧化氮 当心肌梗塞时， 抑郁症是剂量依赖性的。因此，我们研究了 预防性治疗（治疗前）和治疗性治疗 (post TNF激发后用NMA治疗），检查 早期和晚期的时间点。NMA治疗降低了测量值 在早期和晚期的时间点产生一氧化氮。在 早期时间点，给予NMA治疗或 但这并不能预防TNF的副作用。 然而，在用l-精氨酸逆转NMA后24小时， 一氧化氮生成的天然底物，预防性NMA 改善了TNF引起的心功能下降 挑战.这些数据表明TNF对心脏的双重作用， 功能早期效应似乎不依赖于一氧化氮， 而后者的作用似乎是一氧化氮依赖性的。NMA是 与细胞因子疗法一起用于癌症患者， 心血管毒性研究计划在获得性免疫 虚证患者也要这样做。这些研究将 帮助确定这种方法的可行性。

The present investigation has been undertaken to determine, in vivo, if nitric oxide is responsible for cytokine-induced myocardial depression. On the basis of in vitro data, we believe the negative ionotropic effects of cytokines on the heart are mediated by nitric oxide. In isolated hamster cardiac papillary muscle, this negative ionotropic effect of cytokines can be blocked by N-G monomethyl-L-arginine (NMA), a nitric oxide synthase inhibitor. Because the in vitro data demonstrated that nitric oxide synthase inhibitors prevented tumor necrosis factor (TNF)-induced myocardial depression of rapid onset and reversal, we studied a low dose of recombinant human TNF challenge in canines. This TNF challenge produces significant, early, and short-lived myocardial depression (resolved by 24 h). Surprisingly, we found that NMA did not prevent the early (up to 6 h) deleterious effects of TNF on cardiac function. In fact, during this period, TNF and NMA effects on all cardiac and hemodynamic parameters were additive (i.e., NMA did not block TNF effects). However, 24 h after TNF infusion, NMA did ameliorate the effects of TNF on some parameters such as acidbase derangements and decreases in mean arterial pressure and systemic vascular resistance. These data suggest that the early phase of TNF-induced cardiac and vascular abnormalities may not be related to nitric oxide production. However, some of the later effects of TNF may be related to the production of nitric oxide. Given the finding suggestive of a beneficial effect of NMA 24 h post TNF infusion, we evaluated the effects of nitric oxide inhibition in the setting of higher doses of TNF causing longer lasting myocardial depression. Previous experiments using TNF challenges in canines suggest that this is a reasonable hypothesis, (i.e., there may be two phases of cardiac injury). In canines, there is an early (less than 8 h), dose-independent mechanism of myocardial depression and a late (greater than 24 h) dose-dependent mechanism of myocardial depression. It was hypothesized that the inhibition of nitric oxide synthesis might not be advantageous early when myocardial depression is dose dependent. We therefore studied both prophylactic treatment (pretreatment) and therapeutic treatment (post treatment) with NMA after TNF challenge, examining both early and late time points. Treatment with NMA lowered measures of nitric oxide production in both early and late time points. At early time points, NMA given either therapeutically or prophylactically did not prevent the adverse affects of TNF. However, at 24 h, after reversal of the NMA with l-arginine, the natural substrate for nitric oxide production, prophylactic NMA ameliorated the decline in cardiac function seen with TNF challenge. These data suggest a dual effect of TNF on cardiac function. The early effect appears to be nitric oxide independent, while the later effect appears to be nitric oxide dependent. NMA is being used with cytokine therapy for cancer patients to inhibit their cardiovascular toxicity. Studies are planned in acquired immune deficiency syndrome patients to do the same. These studies will help determine the advisability of this approach.