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.
| Barbuti, Andrea; Ishii, Satoshi; Shimizu, Takao et al. (2002) Block of the background K(+) channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor. Am J Physiol Heart Circ Physiol 282:H2024-30 |
