MYOCARDIAL PROTECTION BY NHE-1 INHIBITION

NHE-1 抑制对心肌的保护

基本信息

批准号：
6922874
负责人：
Raul Jaime Gazmuri
金额：
$ 27.3万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2007-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6922874
关键词：
cardiopulmonary resuscitation cardiovascular injury chemoprevention cytoprotection eicosanoids heart disorder chemotherapy high energy compound inhibitor /antagonist ischemia myocardium nonhuman therapy evaluation oxidative stress sodium hydrogen exchanger swine vasomotion ventricular fibrillation

项目摘要

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.

描述（由申请人提供）：当前的建议是针对与与心肌保护机制有关的研究抑制肌膜Na+ -h+交换器同工型-1（NHE-1）。研究是在 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 NHE-1-1抑制后，溶出后的心室异位活性降低，3）NHE-1抑制对心血管和神经系统功能的后期悬浮后影响，以及4）NHE-1抑制作用在VF开始之前对NHE-1抑制作用的影响对随后的复苏和生存。通过测量心肌血流来研究缺血性染色的机制（荧光微球）和封闭式复苏模型中的氧化损伤（异丙烷水平），并在使用心肺旁路的受控冠状血流条件下测量心肌Na+和高能核苷酸。机制通过记录单相作用电位来研究震后的异位活性与NHE-1抑制作用，Na+-ca2+交换器抑制作用和肌膜K+ATP通道有关封锁。通过使用可植入的传感器，测量血压，心电图，温度和迁移率在激发后7天的时间内，评估后期的后震动结果。最后，将NHE-1抑制预处理的效果与在复苏工作期间开始治疗时进行了比较。 VF发作后可以增加结果的干预措施（即使是一小部分）可能会通过挽救数千人生命而产生巨大的公共卫生影响。