MYOCARDIAL PROTECTION BY NHE-1 INHIBITION

描述(由申请人提供)： 目前的建议是研究与以下因素相关的心肌保护机制 抑制肌膜Na-H交换异构体-1(NHE-1)。研究是在一个 建立猪室颤(VF)全身缺血模型，采用常规闭胸复苏或体外循环模拟复苏，根据4个具体目的研究：1)NHE-1抑制VF复苏期间改善缺血性痉挛的机制；2)NHE-1抑制后复苏后心室异位活动降低的机制；3)复苏后晚期NHE-1抑制对心血管和神经功能的影响；4)在VF发生前抑制NHE-1对后续复苏和存活的影响。 通过测量心肌血流量来探讨缺血性肌挛缩的机制 通过在闭胸式复苏模型中检测(荧光微球)和氧化损伤(异前列腺素水平)，以及在使用体外循环控制冠脉血流的条件下测量心肌钠和高能核苷酸。它的作用机制 复苏后异位活动的单相动作电位记录 NHE-1抑制、Na-Ca~(2+)交换器抑制与肌膜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天内的血压、心电图、体温和活动度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处理的效果进行了比较。可以在室颤发作后提高预后的干预措施(即使只是一小部分)可能会通过拯救数千人的生命而产生戏剧性的公共卫生影响。

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.