NITRIC OXIDE SYNTHASE INHIBITORS IN VIVO TNF-INDUCED MYOCARDIAL DEPRESSION

一氧化氮合酶抑制剂体内 TNF 诱导的心肌抑制

• 批准号: 3752179
• 负责人: C 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/3752179
• 关键词: amine oxidoreductase; antiarrhythmic agent; arginine; arrhythmia; blood pressure; dogs; hamsters; heart disorder chemotherapy; injection /infusion; myocardium disorder; nonhuman therapy evaluation; oxidoreductase inhibitor; papillary muscles; recombinant proteins; 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 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.

目前的调查是为了在体内确定是否 一氧化氮参与了细胞因子引起的心肌抑制。这个 细胞因子对心脏的负性变力作用被认为是 由一氧化氮介导，基于体外数据。在隔离的仓鼠中 心脏乳头肌，这种细胞因子的负性变力作用可以 被一氧化氮合酶N-G-单甲基-L-精氨酸阻断 抑制剂。因为体外数据显示一氧化氮合酶 拮抗剂可预防肿瘤坏死因子诱导的心肌抑制 逆转，我们研究了低剂量重组人肿瘤坏死因子在 犬科动物。这种肿瘤坏死因子的剂量产生了显著的、早期的和短暂的 心肌抑制(24小时后消失)。令人惊讶的是，我们发现NMA 不能阻止早期(长达6小时)的肿瘤坏死因子的有害影响 心脏功能。事实上，在这段时间里，肿瘤坏死因子和NMA效应 所有心脏的血流动力学和代谢参数都是相加的(即 NMA不能阻断肿瘤坏死因子的作用)。然而，在注射肿瘤坏死因子后24小时，NMA做了 改善肿瘤坏死因子对酸碱等参数的影响 平均动脉压和全身血管的排列紊乱和降低 抵抗。这些数据表明，肿瘤坏死因子诱导的早期阶段 心脏和其他异常可能与一氧化氮无关 制作。然而，后来，肿瘤坏死因子的一些有害影响可能是 与一氧化氮的产生有关。鉴于这一发现暗示着 NMA在肿瘤坏死因子输注后24小时的有益效果，我们不进行评估 一氧化氮抑制在大剂量脑缺血再灌流中的作用 肿瘤坏死因子和更持久的心肌抑制。以前的实验使用 犬的肿瘤坏死因子挑战表明，这是一个合理的假设， 即心脏损伤的两个阶段。在犬类中，有一个早期的(&lt；8h)， 心肌抑制的剂量依赖机制和晚期(&gt；24小时)， 心肌抑制的剂量依赖机制。有可能是 当心肌梗死早期抑制一氧化氮是不利的 抑郁症是剂量依赖性的。我们现在使用的是45微克的肿瘤坏死因子剂量 /kg，并用40 mg/kg剂量的NMA对动物进行预处理 通过持续输注40毫克/公斤/小时。我们相信这次调查 可以提供有关有害影响的机制的信息 肿瘤坏死因子对心脏功能的影响，可能为 开发新的治疗策略来治疗糖尿病 心血管忧郁症。NMA目前与细胞因子一起使用 癌症患者的治疗，以抑制他们的心血管 毒物。这些研究还将有助于确定 这种方法。