Preventing Resuscitation Injury and Improving Outcomes

预防复苏损伤并改善结果

• 批准号: 6786802
• 负责人: RICHARD E KERBER
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6786802
• 关键词: artificial respiration; cardiopulmonary resuscitation; coronary artery; cytoprotection; heart arrest; histopathology; nitric oxide synthase; nonhuman therapy evaluation; oxidative stress; oxidoreductase inhibitor; swine; tissue /cell culture; vasodilation; ventricular fibrillation

DESCRIPTION (provided by applicant): This application focuses on the prevention of cerebral and myocardial injury during cardiac arrest and resuscitation. Our hypothesis is that a major mechanism of such injury is the nitric oxide-superoxide-peroxynitrite pathway. Our aim is to show that pharmacological modification of this pathway, using nitric oxide synthase inhibitors, both nonselective and neuronal selective, will ameliorate resuscitation injury and thereby enhance survival from cardiac arrest, and preserve post-arrest cerebral and cardiac function. We will test a series of specific hypotheses. We propose that nonselective NOS inhibitors, given during VF cardiac arrest-defibrillation-resuscitation sequences, enhance resumption of spontaneous circulation and improve post-arrest left ventricular performance. Conversely, nitric oxide donors given during arrest and resuscitation exacerbate cardiac resuscitation injury by increasing toxic peroxynitrite generation. We propose to demonstrate, in coronary microvessels and isolated vascular rings, a specific mechanism of cardiac resuscitation injury direct current shock-induced loss of normal endothelial-mediated coronary arterial vasodilation. We will show that NOS inhibitors protect against this mechanism. Finally, in survival experiments, we will show that selective neuronal nNOS inhibition preserves neurologic function 48 hours after cardiac arrest and resuscitation and minimizes histopathological neuronal damage, while nonselective NOS inhibition enhances cardiac performance at 48 hours after arrest. More effective treatment of resuscitation-induced cardiac and brain injury is imperative for improved survival of the estimated 300,000 US victims of cardiac arrest every year.

描述（由申请人提供）： 该应用的重点是预防心脏骤停和复苏期间的脑和心肌损伤。 我们的假设是，这种损伤的主要机制是一氧化氮-超氧化物-过氧亚硝酸盐途径。 我们的目的是证明，使用非选择性和神经元选择性一氧化氮合酶抑制剂对该途径进行药理学修改，将改善复苏损伤，从而提高心脏骤停的生存率，并保留心脏骤停后的脑功能和心脏功能。 我们将测试一系列具体假设。 我们建议，在室颤心脏骤停-除颤-复苏序列期间给予非选择性 NOS 抑制剂，可增强自主循环的恢复并改善心脏骤停后的左心室功能。 相反，在逮捕和复苏期间给予一氧化氮供体会增加有毒过氧亚硝酸盐的产生，从而加剧心脏复苏损伤。 我们打算在冠状微血管和孤立的血管环中证明心脏复苏损伤的特定机制，即直流电休克导致正常内皮介导的冠状动脉血管舒张功能丧失。 我们将证明 NOS 抑制剂可以防止这种机制。 最后，在生存实验中，我们将证明选择性神经元 nNOS 抑制可在心脏骤停和复苏后 48 小时保留神经功能，并将组织病理学神经元损伤降至最低，而非选择性 NOS 抑制可增强心脏骤停后 48 小时的心脏功能。 为了提高美国每年约 300,000 名心脏骤停受害者的生存率，必须对复苏引起的心脏和脑损伤进行更有效的治疗。