REPERFUSION ARRHYTHMIAS--MECHANISMS AND PREVENTION

再灌注心律失常——机制和预防

• 批准号: 2029879
• 负责人: BRIAN F HOFFMAN
• 金额: $ 34.16万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-24 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2029879
• 关键词: arrhythmia; dogs; heart cell; leukocyte activation /transformation; membrane potentials; muscle cells; myocardial ischemia /hypoxia; neutrophil; platelet activating factor; reperfusion; sodium channel; tissue /cell culture; voltage /patch clamp

DESCRIPTION (adapted from the applicant's abstract): The applicant hopes to identify and characterize the role of activated neutrophils in causing arrhythmias during cardiac ischemia and reperfusion and to identify means by which this arrhythmogenic action can be prevented. The applicant will concentrate on reperfusion but believes the results will also be relevant to heart failure. The applicant indicates that preliminary studies show that when neutrophils, bound to single canine myocytes, are activated they cause a reproducible set of changes in the transmembrane potential: generation of runs of early afterdepolarizations and arrest of repolarization. These effects result from formation of platelet-activating factor (PAF) which causes ventricular tachycardia of the in situ canine heart. The applicant will study interactions between canine neutrophils and cardiac myocytes with intracellular electrodes to fully characterize this interaction and evaluate the effects thereon of blockade of PAF receptors, blockade of binding with antibodies to ICAM-1 and CD-18 and inhibition of PAF synthesis with BIRM-270. The mechanism by which PAF causes abnormalities of the transmembrane potential will be demonstrated by patch clamp studies on whole cell and single channel sodium currents. The applicant will extend the studies to the in situ canine heart and use intramyocardial injections of PAF and zymosan-activated serum (an activator of neutrophils) to see if the interventions found effective in vitro block the arrhythmogenic actions of PAF and activated neutrophils or inhibit the neutrophil influx. Finally, the applicant will evaluate the effective interventions against reperfusion arrhythmias.

描述（根据申请人的摘要改编）：申请人希望 识别并表征激活的中性粒细胞在引起的作用 心脏缺血和再灌注期间心律不齐，并通过 可以预防这种心律失常作用。 申请人将 专注于再灌注，但认为结果也将与 心脏衰竭。 申请人表明初步研究表明 当中性粒细胞与单犬肌细胞结合时，它们会引起 一组可再现的跨膜电位变化：生成 早期过时的术和重极化的停滞。 这些 作用是由血小板激活因子（PAF）形成的影响 引起原位犬心的心室心动过速。 申请人 将研究犬嗜中性粒细胞与心肌细胞之间的相互作用 细胞内电极充分表征这种相互作用并评估 其封锁PAF受体的效果，与结合的封锁 ICAM-1和CD-18的抗体以及对PAF合成的抑制作用 BIRM-270。 PAF引起异常的机制 跨膜电位将通过斑块夹的整体研究来证明 细胞和单个通道钠电流。 申请人将扩展 对原位犬心脏进行研究，并使用心膜内注射 PAF和Zymosan激活的血清（中性粒细胞的激活剂），以查看是否是否 干预措施发现在体外有效阻止 PAF和激活的中性粒细胞或抑制中性粒细胞的流入。 最后， 申请人将评估针对再灌注的有效干预措施 心律不齐。