This new application for three years of support has the long term objective to investigate mechanisms for modified ion channel function in cardiac ischemia. The ischemic metabolite lysophosphatidylcholine (LPC) has long been implicated as a key mediator of electrophysiological changes and arrhythmias in acute ischemia. Indirect evidence has suggested that both LPC and ischemia disturb the cytoskeleton. The cytoskeleton disrupting agent cytochalasin modified Na channel gating similarly to that of how LPC. This suggests that the mechanism for the LPC effect on Na channels may be through the cytoskeleton. Alternatively, LPC may act through a mechanism not involving the cytoskeleton such as lipid channel protein interactions or direct effects. LPC has been little studied at the cellular level, and the role of the cytoskeleton in cardiac ion channels gating is unknown. Both are likely to be important links in the pathogenesis of ischemia. In this proposal, the kinetics of LPC-modified cardiac Na channels will be fully described by patch clamping isolated rat and rabbit cardiac cells (Aim 1). The role of the cytoskeleton in Na channel gating will be investigated by using cytoskeleton disrupting (e.g., colchicine, cytochaIasin) and stabilizing (e.g., phalloidin and taxol) agents, cytoskeleton elements (actin, spectrin and linkage protein ankyrin) and antibodies to these elements (Aim 2). The interaction of antiarrhythmic drugs (lidocaine, flecainide, quinidine) with these modified channels will be studied by patch clamp (Aim 3). Mathematical models will be used for both channel gating and drug-channel interaction. These results may help explain why ischemic tissue is apparently more sensitive to the action of some antiarrhythmic drugs as well as cytoskeleton role in Na channel function. Since cardiac arrhythmias ischemic heart disease remain major public health problems, knowledge of the underlying mechanisms may lead to better understanding of cardiac arrhythmias and provide insight into treatment.
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