THE IMPORTANT ROLES OF MEDIATORS IN ENDOTOXIN-INDUCED CARDIOVASCULAR ALTERATIONS

介质在内毒素引起的心血管改变中的重要作用

基本信息

批准号：
11670671
负责人：
IWASE Mitsunori
金额：
$ 1.98万
依托单位：
NAGOYA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

This study evaluates the time course of the alterations in LV dimensions, LV wall thickness and LV systolic function in rats with endotoxemia using echocardiography as well as the myocardial histopathological findings. Our second goal is to examine whether pretreatment with a platelet activating factor (PAF) antagonist would ameliorate the LPS-induced cadiov as cular collapse.Subjects : and Interventions : Male, Wistar rats were used (8 to 9 weeks old, n=56). In pentobarbital-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein was also catheterized for the administration of drugs. LPS (2mg/kg) derived from Klebsiella pneumoniae or physiological saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with a 8-13MHz transducer.Measurements and Main Results : LPS administration immediately produced pro … More gressive hypotension. The maximal hypotensive response was observed at 10 minutes after LPS infusion with mean arterial pressure (MAP) falling from 119±2 to 56±3mmHg (p<0.001). LV end-diastolic internal dimension decreased from 6.4±0.1 to 3.1±0.1 mm (p<0.001) at 30 minutes after LPS and remained significantly reduced as compared with control rats receiving saline. LV end-systolic dimension also decreased dramatically from3.5±0.2 to 0.5±0.1 mm (p<0.001) at 30 minutes after LPS, and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45±1 to 84±2 % (p<0.001) at 30 minutes after LPS, and remained elevated as compared with control rats. LV wall thickness of the interventricular septum and the posterior wall increased strikingly from 15 minutes until 2 hours after LPS infusion. Pathological studies revealed marked congestion of capillaries and mild edema in the LV myocardium. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma levels of epinephrine and norepinephine. There was no elevation of concentrations of NOx (nitrite and nitrate) or adenosine.Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated changes in LV function. TCV-309 administration abolished the LPS-mediated elevation of the plasma level of norepinephrine and reduced the plasma level of epinephrine.Conclusions The hypotension that occurred in the early phase of LPS-induced shock was accompanied by cardiac functional and structural alterations. The marked increase in LV wall thickness can be ascribed to the congestion of capillaries and edema in the LV myocardium. PAF plays an important role in the early phase of LPS-induced cardiov ascular responses. Less

本研究使用超声心动图评估内毒素血症大鼠左心室尺寸、左心室壁厚度和左心室收缩功能变化的时间过程以及心肌组织病理学结果，以检查是否使用血小板激活因子（PAF）进行预处理。拮抗剂会改善 LPS 诱导的眼球塌陷等心血管疾病。受试者：和干预措施：使用雄性 Wistar 大鼠（8 至 9 周）在戊巴比妥麻醉的大鼠中，将插管插入右颈动脉以测量动脉血压并采集血液样本以施用LPS（2mg/kg）。在有或没有 TCV-309（一种特异性强效 PAF 拮抗剂）预处理的情况下，使用来自肺炎克雷伯菌的药物或生理盐水进行超声心动图研究。 8-13MHz 传感器。测量和主要结果：LPS 给药立即产生渐进性低血压，在 LPS 输注后 10 分钟观察到最大低血压反应，平均动脉压 (MAP) 从 119±2 降至 56±3mmHg (p)。 <0.001）。左心室舒张末期内部尺寸从 6.4±0.1 减小至 3.1±0.1 毫米。 LPS 后 30 分钟，左心室收缩末期尺寸与接受盐水的对照大鼠相比，仍显着降低（p<0.001），LPS 后 30 分钟，左心室收缩末期尺寸也从 3.5±0.2 毫米显着降低至 0.5±0.1 毫米（p<0.001）。，并在整个实验过程中保持显着降低，从 45±1 % 增加到 84±2 % (p<0.001)。 LPS 后 30 分钟，与对照大鼠相比，左室间隔和后壁的厚度从 LPS 输注后 15 分钟到 2 小时显着增加。血浆肾上腺素和去甲肾上腺素水平升高表明，LPS 显着增加了交感神经张力，但 NOx（亚硝酸盐和去甲肾上腺素）浓度没有升高。使用 TCV-309（一种特异性强效 PAF 拮抗剂）进行预处理，可减少 LPS 引起的低血压并减弱 LV 功能的变化，TCV-309 给药消除了 LPS 介导的血浆去甲肾上腺素水平升高并降低了血浆水平。结论 LPS诱发休克早期发生的低血压伴随着心脏功能和结构的改变，左心室壁显着增大。左心室心肌毛细血管充血和水肿在脂多糖诱导的心血管反应早期起重要作用。