Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I.
Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I.
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DOI：
10.1161/circulationaha.109.853267
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发表时间：
2009-09-08
期刊：
影响因子：
37.8
通讯作者：
Gladwin MT
中科院分区：
文献类型：
--
作者：
Dezfulian C;Shiva S;Alekseyenko A;Pendyal A;Beiser DG;Munasinghe JP;Anderson SA;Chesley CF;Vanden Hoek TL;Gladwin MT
四分之三的心脏骤停幸存者在出院前死亡或遭受严重的神经损伤。除了治疗性低温和血运重建外，还没有开发出新的治疗方法来改善复苏后的存活率或心脏和神经功能。亚硝酸盐（NO2−）增加细胞对多器官局灶性缺血再灌注损伤的恢复力。我们假设亚硝酸盐治疗可以改善心肺骤停这一独特的全脑缺血再灌注损伤后的预后。我们开发了一种小鼠心脏骤停模型，其特征在于12分钟的常温心搏停止和高心肺复苏（CPR）率。在该模型中，全身缺血和CPR与血液和器官亚硝酸盐耗竭、可逆性心肌功能障碍、肺泡气体交换受损、神经损伤和约50%的死亡率相关。与在CPR开始时给予的设盲生理盐水安慰剂相比，单次低剂量静脉内亚硝酸盐（50 nmol=1.85 μmol/kg=0.13 mg/kg）与肾上腺素改善了心脏功能、生存率和神经学结局。从机制的角度来看，亚硝酸盐治疗恢复心内亚硝酸盐和增加S-亚硝基硫醇水平，减少病理性心脏线粒体氧消耗由于活性氧的形成，并通过可逆的特异性抑制呼吸链复合物I防止氧化酶损伤。心搏停止12分钟后复苏后，亚硝酸盐治疗可快速可逆地调节早期再灌注期间线粒体活性氧的产生，限制急性心功能不全和死亡，以及幸存者的神经损伤。
Three-fourths of cardiac arrest survivors die prior to hospital discharge or suffer significant neurological injury. Excepting therapeutic hypothermia and revascularization, no novel therapies have been developed that improve survival or cardiac and neurological function after resuscitation. Nitrite (NO2−) increases cellular resilience to focal ischemia-reperfusion injury in multiple organs. We hypothesized that nitrite therapy may improve outcomes after the unique global ischemia-reperfusion insult of cardiopulmonary arrest. We developed a mouse model of cardiac arrest characterized by 12-minutes of normothermic asystole and a high cardiopulmonary resuscitation (CPR) rate. In this model, global ischemia and CPR was associated with blood and organ nitrite depletion, reversible myocardial dysfunction, impaired alveolar gas exchange, neurological injury and an approximate 50% mortality. A single low dose of intravenous nitrite (50 nmol=1.85 μmol/kg=0.13 mg/kg) compared to blinded saline placebo given at CPR initiation with epinephrine improved cardiac function, survival and neurological outcomes. From a mechanistic standpoint, nitrite treatment restored intracardiac nitrite and increased S-nitrosothiol levels, decreased pathological cardiac mitochondrial oxygen consumption due to reactive oxygen species formation and prevented oxidative enzymatic injury via reversible specific inhibition of respiratory chain complex I. Nitrite therapy after resuscitation from 12-minutes of asystole rapidly and reversibly modulated mitochondrial reactive oxygen species generation during early reperfusion, limiting acute cardiac dysfunction and death, as well as neurological impairment in survivors.