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

一氧化氮合酶抑制剂对体内肿瘤坏死因子诱导的作用

• 批准号: 6431772
• 负责人: CHARLES NATANSON
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431772
• 关键词: arginine; blood toxicology; dogs; dosage; hamsters; heart disorder chemotherapy; heart function; heart metabolism; hemodynamics; injection /infusion; myocardium disorder; nitric oxide synthase; nonhuman therapy evaluation; oxidoreductase inhibitor; tumor necrosis factor alpha; vascular resistance

The present investigation has been undertaken to determine, in vivo, if nitric oxide is responsible for cytokine-induced myocardial depression. The negative ionotropic effects of cytokines on the heart are believed to be mediated by nitric oxide, based on in vitro data. 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 demonstrates 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 6h) deleterious effects of TNF on cardiac function. In fact, during this time 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 acid-base 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 suggestive finding 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. Therefore, we studied both prophylactic treatment (pretreatment) or therapeutic treatment with NMA (post-treatment 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 hour, 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. In future studies, we plan to confirm these findings in actual bacterial infection-induced myocardial depression models. NMA is being used with cytokine therapy for cancer patients to inhibit their cardiovascular toxicity and studies are planned in AIDS patients to do the same. These studies will help determine the advisability of this approach.

目前的调查已进行，以确定在体内，如果一氧化氮是负责的苦参碱诱导的心肌抑制。基于体外数据，细胞因子对心脏的负离子效应被认为是由一氧化氮介导的。在离体仓鼠心脏乳头肌中，细胞因子的这种负离子效应可被一氧化氮合酶抑制剂N-G单甲基-L-精氨酸（NMA）阻断。由于体外数据表明，一氧化氮合酶抑制剂防止肿瘤坏死因子（TNF）诱导的心肌抑制的快速发病和逆转，我们研究了低剂量的重组人TNF的挑战犬。这种TNF激发产生显著的、早期的和短暂的心肌抑制（在24小时内消退）。令人惊讶的是，我们发现NMA不能预防TNF对心脏功能的早期（长达6小时）有害影响。事实上，在这段时间内，TNF和NMA对所有心脏和血液动力学参数的影响是累加的（即，NMA不阻断TNF作用）。然而，TNF输注后24 h，NMA确实改善了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的早期阶段可能与一氧化氮的产生无关。然而，TNF的一些后期效应可能与一氧化氮的产生有关。鉴于TNF输注后24小时NMA的有益作用的提示性发现，我们评估了在较高剂量TNF引起较长持续心肌抑制的情况下一氧化氮抑制的作用。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，心脏损伤可能有两个阶段。在犬中，存在早期（小于8小时）、剂量非依赖性心肌抑制机制和晚期（大于24小时）、剂量依赖性心肌抑制机制。假设当心肌抑制具有剂量依赖性时，一氧化氮合成的抑制在早期可能不是有利的。因此，我们研究了NMA的预防性治疗（治疗前）或治疗性治疗（TNF激发后的治疗后，检查早期和晚期时间点）。NMA治疗降低了早期和晚期一氧化氮产生的指标。在早期时间点，治疗性或非治疗性给予的NMA不能预防TNF的不良影响。然而，在24小时时，在用L-精氨酸（一氧化氮产生的天然底物）逆转NMA后，预防性NMA改善了TNF激发所见的心功能下降。这些数据表明TNF对心脏功能具有双重作用。早期效应似乎是一氧化氮独立的，而后期效应似乎是一氧化氮依赖性的。在未来的研究中，我们计划在实际的细菌感染诱导的心肌抑制模型中证实这些发现。NMA正与细胞因子疗法一起用于癌症患者，以抑制其心血管毒性，并计划在艾滋病患者中进行研究，以实现同样的目的。这些研究将有助于确定这种方法的可行性。