REPERFUSION ARRHYTHMIAS--MECHANISMS AND PREVENTION

描述(改编自申请人的摘要)：申请人希望 确定和表征激活的中性粒细胞在导致 心脏缺血和再灌流期间的心律失常，并通过 这种致心律失常的行为是可以预防的。申请者将会 专注于再灌注，但相信结果也将与 心力衰竭。申请人表示，初步研究表明 当与单个犬肌细胞结合的中性粒细胞被激活时，它们会导致 一组可复制的跨膜电位变化：产生 早期后除极和复极停止。这些 作用是由于血小板激活因子(PAF)的形成 导致犬原位心室性心动过速。申请人 将研究犬中性粒细胞与心肌细胞之间的相互作用 细胞内电极来充分描述这种相互作用并评估 阻断PAF受体、阻断与PAF的结合对其影响 抗ICAM-1和CD-18抗体及对PAF合成的抑制 BIRM-270。房颤引起心脏功能异常的机制 跨膜电位将通过膜片钳研究总体上得到证实 细胞和单通道钠电流。申请者将延长 犬原位心脏的研究及心肌内注射的应用 PAF和酵母多糖激活的血清(一种中性粒细胞的激活剂)，看看是否 体外有效的干预措施可阻断阿司匹林致心律失常的作用 PAF和激活的中性粒细胞或抑制中性粒细胞内流。最后， 申请人将评估针对再灌注的有效干预措施。 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.