NITRIC OXIDE SYNTHASE INHIBITORS IN VIVO TNF-INDUCED MYOCARDIAL DEPRESSION

本研究旨在体内确定， 一氧化氮是苦参碱引起的心肌抑制的原因。 的 细胞因子对心脏的负性变力作用被认为是 介导的一氧化氮，基于体外数据。 在隔离仓鼠 心脏乳头肌，细胞因子的这种负性变力作用可以 被N-G-单甲基-L-精氨酸（NMA）（一种一氧化氮合酶）阻断 抑制剂. 因为体外数据显示一氧化氮合酶 抑制剂可防止TNF诱导的心肌抑制快速发作， 逆转，我们研究了低剂量的重组人TNF攻击， 犬齿 该TNF剂量产生显著的、早期的和短暂的 心肌抑制（24小时内消退）。 令人惊讶的是，我们发现NMA 并不能阻止TNF的早期（最多6小时）有害作用， 心脏功能 事实上，在此期间，TNF和NMA的作用 对所有心脏血流动力学和代谢参数的影响是累加的（即， NMA不阻断TNF作用）。 然而，TNF输注后24小时，NMA 改善TNF对酸碱平衡等指标的影响 平均动脉压和全身血管的紊乱和降低 阻力 这些数据表明，TNF诱导的早期阶段 心脏和其他异常可能与一氧化氮无关 生产 然而，后来，TNF的一些有害作用可能是 与一氧化氮的产生有关。 鉴于这一发现暗示了 TNF输注后24小时NMA的有益作用，我们未评估 一氧化氮抑制在较高剂量的 TNF和持续时间更长的心肌抑制。 以前的实验使用 犬中的TNF激发表明这是一个合理的假设， 即心脏损伤的两个阶段 在犬科动物中，有一个早期（<8小时）， 心肌抑制的剂量非依赖性机制和晚期（> 24小时）， 心肌抑制的剂量依赖性机制。 有可能 当心肌缺血时， 抑郁症是剂量依赖性的。 我们现在使用的TNF剂量是45微克 /kg，然后用40 mg/kg推注剂量的NMA预处理动物 连续输注40 mg/kg/h。 我们相信这次调查 可以提供有关有害影响机制的信息 TNF对心功能的影响，可能为 开发新的治疗策略， 心血管抑郁症 NMA目前与细胞因子一起使用 治疗癌症患者，以抑制他们的心血管疾病， 毒性 这些研究还将有助于确定 这种方法。

The present investigation has been undertaken to determine, in vivo, if nitric oxide is responsible for cytokine-induced myocardial depress. The negative inotropic effect 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 inotropic effect of cytokines can be blocked by N-G-monomethyl-L-arginine (NMA), a nitric oxide synthase inhibitor. Because the in vitro data shows that nitric oxide synthase inhibitors prevented TNF-induced myocardial depression of rapid onset and reversal, we studied a low dose of recombinant human TNF challenge in canines. This TNF dose 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 time period, TNF and NMA effects on all cardiac hemodynamic and metabolic 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 other abnormalities may not be related to nitric oxide production. However, later, some deleterious effects of TNF may be related to production of nitric oxide. Given the finding suggestive of a beneficial effect of NMA at 24 h post TNF infusion, we are not evaluating the effect of nitric oxide inhibition in the setting of higher doses of TNF, and longer lasting myocardial depression. Previous experiments using TNF challenges in canines suggest that this is a reasonable hypothesis, i.e. two phases of cardiac injury. In canines, there is an early (<8h), dose independent mechanism of myocardial depression and a late (>24h), dose dependent mechanism of myocardial depression. It is possible that inhibition of nitric oxide is not advantageous early when myocardial depression is dose dependent. We are now using TNF doses of 45 microg /kg, and pretreating animals with doses of NMA of 40 mg/kg bolus followed by continuous infusion of 40 mg/kg/h. We believe that this investigation could provide information about the mechanism of the deleterious effects of TNF on cardiac function, could potentially provide the basis for the development of new therapeutic strategies for the treatment of cardiovascular depression. NMA is presently being used with cytokine therapies for cancer patients in order to inhibit their cardiovascular toxicities. These studies will also help determine the advisability of this approach.