MYOCARDIAL PROTECTION BY NHE-1 INHIBITION

描述（由申请人提供）： 目前的提案是研究与心肌保护相关的机制 抑制肌膜 Na -H 交换异构体-1 (NHE-1)。 研究是在一个 心室颤动（VF）引起的全身缺血的猪模型，其中尝试使用传统的闭胸复苏或使用外周心肺转流模拟复苏，根据四个具体目标设计用于研究1）NHE-1抑制在VF复苏过程中改善缺血性挛缩的机制，2）NHE-1抑制后复苏后心室异位活动减少的机制， 3) NHE-1 抑制对心血管和神经功能的晚期复苏后影响，以及 4) 在心室颤动发作前进行 NHE-1 抑制对随后的复苏和生存的影响。 通过测量心肌血流量研究缺血性挛缩的机制 （荧光微球）和氧化损伤（异前列腺素水平）在闭胸复苏模型中，并通过在使用心肺旁路控制冠状动脉血流的条件下测量心肌钠和高能核苷酸。 其机制 通过记录单相动作电位来研究复苏后的异位活动 与 NHE-1 抑制、Na -Ca2 交换器抑制和肌膜 K ATP 通道的关系 封锁。 通过使用植入式传感器测量复苏后 7 天的血压、心电图、体温和活动能力来评估复苏后的晚期结果。 最后，将 NHE-1 抑制预处理的效果与复苏过程中开始治疗的效果进行比较。 能够改善心室颤动（即使是一小部分）发作后的预后的干预措施可能会挽救数千人的生命，从而产生巨大的公共健康影响。

DESCRIPTION (provided by applicant): The current proposal is for studies on the mechanisms of myocardial protection associated with inhibition of the sarcolemmal Na+-H+ exchanger isoform-1 (NHE-1). Studies are conducted in a porcine model of whole-body ischemia induced by ventricular fibrillation (VF) in which resuscitation is either attempted using conventional closed-chest resuscitation or simulated using peripheral cardiopulmonary bypass, according to four specific aims designed to study 1) the mechanisms by which NHE-1 inhibition ameliorates ischemic contracture during resuscitation from VF, 2) the mechanisms by which post-resuscitation ventricular ectopic activity is reduced after NHE-1inhibition, 3) the late post-resuscitation effects of NHE-1 inhibition on cardiovascular and neurological function, and 4) the effects of NHE-1 inhibition when instituted before the onset of VF on subsequent resuscitation and survival. The mechanisms of ischemic contracture are investigated by measuring myocardial blood flow (fluorescent microspheres) and oxidative injury (isoprostane levels) in a closed-chest resuscitation model and by measuring myocardial Na+ and high-energy nucleotides under conditions of controlled coronary blood flow using cardiopulmonary bypass. The mechanisms of post-resuscitation ectopic activity are investigated by recording monophasic action potentials in relation to NHE-1 inhibition, Na+-Ca2+ exchanger inhibition, and sarcolemmal K+ATP channel blockade. The late post-resuscitation outcome is assess by using implantable sensors measuring blood pressure, the electrocardiogram, temperature, and mobility over a period of 7 days post-resuscitation. Finally, the effects of pretreatment with NHE-1 inhibition are compared with those when treatment is started during the resuscitation effort. Interventions that can increase outcome after onset of VF (even by a small fraction) could have a dramatic public health effect by saving thousands of lives.