Bradykinin Receptor Antagonism During Cardiopulmonary Bypass

体外循环期间缓激肽受体拮抗作用

基本信息

批准号：
7644323
负责人：
Mias Pretorius
金额：
$ 40.23万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-08 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7644323
关键词：
Allogenic Alteplase Angiotensin-Converting Enzyme Inhibitors Animals Antihypertensive Agents Attenuated Blood Vessels Bradykinin Bradykinin B2 Receptor Bradykinin Receptor Cardiac Surgery procedures Cardiopulmonary Bypass Controlled Clinical Trials Coronary Arteriosclerosis Coronary Artery Bypass Data Enzyme Inhibition Equilibrium Fibrinolysis Hypotension Inflammation Inflammatory Inflammatory Response Interruption Kallikrein-Kinin System Laboratories Mediating Metabolism Morbidity - disease rate Neutrophil Infiltration Nitric Oxide Organ Transplantation Patients Peptidyl-Dipeptidase A Perioperative Pharmaceutical Preparations Placebo Control Protamines Randomized Receptor, Angiotensin, Type 1 Renin-Angiotensin System Reperfusion Therapy Risk Role Sepsis Sepsis Syndrome Smoking Testing Transfusion Vascular Permeabilities base blood product cytokine hemodynamics mortality pressure receptor response

项目摘要

DESCRIPTION (provided by applicant): Each year over a million patients worldwide undergo cardiac surgery requiring cardiopulmonary bypass (CPB). CPB is associated with significant morbidity including the transfusion of allogenic blood products, inflammation and hemodynamic instability. In fact, approximately 20% of all blood products transfused are associated with coronary artery bypass grafting procedures. Transfusion of allogenic blood products is associated with well-documented morbidity and increased mortality after cardiac surgery. Enhanced fibrinolysis contributes to increased blood product transfusion in the perioperative period. CPB activates the kallikrein-kinin system (KKS), leading to increased bradykinin concentrations. Bradykinin, acting through its B2 receptor, stimulates the release of nitric oxide, inflammatory cytokines and tissue-type plasminogen activator (t-PA). Based on data indicating that angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients with coronary artery disease, many patients undergoing CPB are taking ACE inhibitors. While interruption of the renin-angiotensin system (RAS) reduces inflammation in response to CPB, ACE inhibitors also potentiate the effects of bradykinin. The current proposal derives from data from our laboratory and others elucidating the role of the KKS in the inflammatory, hypotensive and fibrinolytic response to CPB. Specifically, we have found that CPB activates the KKS and that ACE inhibition and smoking further increases bradykinin concentrations. During CPB, bradykinin concentrations correlate inversely with mean arterial pressure and directly with t-PA. Moreover, we have found that bradykinin receptor antagonism attenuates protamine-related hypotension following CPB. The current proposal tests the central hypothesis that endogenous bradykinin contributes to the hemodynamic, fibrinolytic and inflammatory response to CPB and that bradykinin receptor antagonism will reduce hypotension, inflammation and transfusion requirements. In SPECIFIC AIM 1 we will test the hypothesis that the fibrinolytic and inflammatory response to CPB differ during ACE inhibition and angiotensin II type 1 receptor antagonism. In SPECIFIC AIM 2 we will test the hypothesis that bradykinin B2 receptor antagonism attenuates the hemodynamic, fibrinolytic, and inflammatory response to CPB. In SPECIFIC AIM 3 we will test the hypothesis that bradykinin B2 receptor antagonism reduces the risk of allogenic blood product transfusion in patients undergoing CPB. These studies promise to provide important information regarding the effects of drugs that interrupt the RAS and generate new strategies to reduce morbidity in patients undergoing CPB.

描述（由申请人提供）：全世界每年有超过100万名患者接受心脏手术，需要心肺旁路（CPB）。 CPB与明显的发病率有关，包括同源血液产物的输血，炎症和血流动力学不稳定。实际上，大约20％的所有血液产物输血都与冠状动脉搭桥手术有关。同种异性血产品的输血与有据可查的发病率和心脏手术后死亡率增加有关。增强的纤维蛋白解会导致围手术期的血液产物输血增加。 CPB激活Kallikrein-Kinin系统（KKS），从而导致心动激素浓度升高。通过其B2受体作用的松曲蛋白刺激一氧化氮，炎性细胞因子和组织型纤溶酶原激活剂（T-PA）的释放。基于数据表明血管紧张素转化酶（ACE）抑制剂降低了冠状动脉疾病患者的死亡率，许多接受CPB的患者正在服用ACE抑制剂。肾素 - 血管紧张素系统（RAS）的中断会减少对CPB的炎症，而ACE抑制剂也会增强Bradykinin的作用。当前的提案来自我们实验室的数据，其他提案阐明了KKS在炎症，降压和纤维蛋白水解对CPB中的作用。具体而言，我们发现CPB激活KKS，而ACE抑制和吸烟进一步增加了心动激肽的浓度。在CPB期间，心动激素浓度与平均动脉压成反，直接与T-PA相关。此外，我们发现Bradykinin受体拮抗作用会减弱CPB后与精胺相关的低血压。当前的提案检验了中心假设，即内源性心动激肽有助于对CPB的血液动力学，纤维蛋白水解和炎症反应，而松曲素受体拮抗作用将减少降低，炎症和输血需求。在特定目的1中，我们将测试以下假设：在ACE抑制和血管紧张素II型1型受体拮抗过程中，对CPB的纤维蛋白水解和炎症反应有所不同。在特定目标2中，我们将测试Bradykinin B2受体拮抗作用的假设减弱了对CPB的血液动力学，纤维蛋白水解和炎症反应。在特定目标3中，我们将检验以下假设：Bradykinin B2受体拮抗作用降低了接受CPB患者的同性血产品输血的风险。这些研究有望提供有关中断RAS的药物影响并产生新策略以减少CPB患者发病率的重要信息。