Department of Medicine, Division of Pulmonary and Critical Care Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Nitric Oxide. 2012 May 15;26(4):241-50. doi: 10.1016/j.niox.2012.03.007. Epub 2012 Mar 30.
Cardiac arrest results in significant mortality after initial resuscitation due in most cases to ischemia-reperfusion induced brain injury and to a lesser degree myocardial dysfunction. Nitrite has previously been shown to protect against reperfusion injury in animal models of focal cerebral and heart ischemia. Nitrite therapy after murine cardiac arrest improved 22 h survival through improvements in myocardial contractility. These improvements accompanied transient mitochondrial inhibition which reduced oxidative injury to the heart. Based on preliminary evidence that nitrite may also protect against ischemic brain injury, we sought to test this hypothesis in a rat model of asphyxia cardiac arrest with prolonged survival (7d). Cardiac arrest resulted in hippocampal CA1 delayed neuronal death well characterized in this and other cardiac arrest models. Nitrite therapy did not alter post-arrest hemodynamics but did result in significant (75%) increases in CA1 neuron survival. This was associated with increases in hippocampal nitrite and S-nitrosothiol levels but not cGMP shortly after therapy. Mitochondrial function 1h after resuscitation trended towards improvement with nitrite therapy. Based on promising preclinical data, the first ever phase I trial of nitrite infusions in human cardiac arrest survivors has been undertaken. We present preliminary data showing low dose nitrite infusion did not result in hypotension or cause methemoglobinemia. Nitrite thus appears safe and effective for clinical translation as a promising therapy against cardiac arrest mediated heart and brain injury.
心脏骤停导致初始复苏后死亡率显著升高，这主要归因于缺血再灌注引起的脑损伤，以及心肌功能障碍的较小程度。亚硝酸盐以前在局灶性脑和心脏缺血的动物模型中被证明可以预防再灌注损伤。在小鼠心脏骤停后进行亚硝酸盐治疗通过改善心肌收缩力来提高 22 小时的存活率。这些改善伴随着短暂的线粒体抑制，从而减少了心脏的氧化损伤。基于亚硝酸盐可能也可以预防缺血性脑损伤的初步证据，我们试图在具有延长生存时间（7 天）的窒息性心脏骤停大鼠模型中测试这一假设。心脏骤停导致海马 CA1 神经元延迟性死亡，这在该模型和其他心脏骤停模型中得到了很好的描述。亚硝酸盐治疗并未改变心脏骤停后的血液动力学，但确实导致 CA1 神经元存活率显著增加（75%）。这与海马亚硝酸盐和 S-亚硝基硫醇水平的增加有关，但在治疗后不久与 cGMP 无关。复苏后 1 小时的线粒体功能趋势上随着亚硝酸盐治疗而改善。基于有前景的临床前数据，首次对人类心脏骤停幸存者进行了亚硝酸盐输注的 I 期临床试验。我们提出了初步数据，表明低剂量亚硝酸盐输注不会导致低血压或引起高铁血红蛋白血症。因此，亚硝酸盐似乎安全有效，可作为一种有前途的针对心脏骤停介导的心脏和大脑损伤的治疗方法进行临床转化。
