REPERFUSION ARRHYTHMIAS--MECHANISMS AND PREVENTION

描述（改编自申请人摘要）：申请人希望 识别和表征活化的中性粒细胞在引起 心脏缺血和再灌注期间的心律失常，并通过 从而可以防止这种致肿瘤作用。 申请人将 专注于再灌注，但相信结果也将与 心衰 申请方表示，初步研究表明， 当中性粒细胞与单个犬肌细胞结合时， 一组可重复的跨膜电位变化： 早期后除极和复极停滞。 这些 血小板活化因子（PAF）的形成导致了这种效应， 引起犬心脏的室性心动过速。 申请人 将研究犬中性粒细胞和心肌细胞之间的相互作用， 细胞内电极，以充分表征这种相互作用， 阻断PAF受体、阻断与 ICAM-1和CD-18的抗体和PAF合成的抑制， BIRM-270。 PAF引起肺动脉异常的机制 跨膜电位将通过膜片钳研究整体证明 细胞和单通道钠电流 申请人将延长 在原位犬心脏的研究，并使用心肌内注射 PAF和酵母多糖激活的血清（中性粒细胞的激活剂），看看是否 在体外发现有效的干预措施阻断了 PAF与激活的中性粒细胞或抑制中性粒细胞流入。 最后， 申请人将评估针对再灌注的有效干预 心律不齐

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.