The proposed work will examine calcium-dependent and triggered arrhythmias in heart muscle. This study will investigate links between the intracellular concentrations of free calcium ions (aiCa), sodium ions (aiNa) and hydrogen ions (pHi) and normal and arrhythmogenic electrical properties of heart. Examination of tissue under voltage clamp will be carried out to determine which ionic currents have been altered during arrhythmogenesis and to what extent each membrane current component is responsible for the generation of the abnormal electrical activity. Experiments will make use of recently developed methods to study membrane potential, membrane current and aiNa, aiCa and pHi. Two experimental preparations will be used. (1). Single ventricular muscle cells from rat and guinea pig (enzymatically dissociated) will be voltage-clamped using a single-microelectrode method. In the single cell experiments the calcium-sensitive fluorescent indicator fura-2 will be used to measue aiCa while the H+ sensitive fluorescent indicator BCECF will be used to measure pHi. Video imaging techniques will be used to measure levels and spatial variations of aiCa and of phi. (2). Sheep Purkinje fibers will be examined using a two-microelectrode voltage-clamp method while measuring tension, aiCa (using the calcium- activated photoprotein aequorin), and aiNa and pHi (using ion- selective microeletrodes). This combination of new techniques and established methods will permit us, for the first time, to examine quantitatively the ionic control of membrane currents in myocardium and in Purkinje fibers under normal and arrhythmogenic conditions. The planned experiments will address the following questions: 1. What is the role of the calcium-activated current ITI in the genesis of cardiac arrhythmias? 2. What cellular processes give rise to ITI? Is this current generated by a calcium-activated channel? 3. How do interactions between the normal calcium current (ICa) and ITI affect arrhythmogenesis in heart? 4. How do Na-Channel blockers and Ca-channel blockers effect ITI? Do the agents act directly on the ITI current pathway? Do they affect ITI by altering intracellular ion activity? Do they only decrease excitability? The proposed research should broaden our understanding of the cellular mechanisms that regulate the normal heartbeat and underlie the development of arrhythmias. Furthermore, by revealing the ionic and cellular basis of certain cardiac rhythm disturbances, this work should lay the foundation for the development of new drugs and improved application of the currently used therapeutic agents and diagnostic techniques.
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