The objective of this application is the study of the mechanism of overdrive excitation (namely, the induction or acceleration of fast spontaneous activity by a fast drive) in several cardiac tissues.
The specific aims are directed to the analysis of the following phenomena and their underlying mechanisms: overdrive excitation in the sinus node; the respective roles of diastolic depolarization and the oscillatory potential in overdrive excitation; the oscillatory current in the sinus node; the metabolic dependance of the oscillatory current; overdrive excitation in ventricular muscle fibers; the prevention or abolition of overdrive excitation in cardiac tissues; the oscillatory potential as the cause of early after depolarizations; the decrease in the magnitude of the oscillatory potential with increasing calcium overload. By using different techniques and experimental approaches, information will be sought with the aim of enhancing the understanding of the electrical disturbances caused by calcium overload in cardiac tissues and their relation to the induction of arrhythmias. The experiments will be conducted in different isolated perfused cardiac tissues. Several techniques will be employed. Transmembrane potentials and contractile force will be recorded by means of a microelectrode technique and a force transducer, respectively. A two microelectrode voltage clamp technique will be applied to study the oscillatory current under different conditions in shortened sinus node strips and shortened Purkinje fibers. The intracellular sodium ion activity will be recorded at the same time as the action potential and the twitch. The experiments involve the analysis of the electrical events underlying overdrive excitation in the different tissues, the correlation between electrical and mechanical events (oscillatory potentials and after contractions), manipulation of the extracellular and intracellular ionic environment, the block of specific ionic channels, the separation of electrical events by selective blockers of different currents, the study of the oscillatory current and its characteristics in the sinus node, the factors affecting the oscillatory potential and the oscillatory current including their metabolic dependance, the study of the factors which are important for the prevention or abolition of overdrive excitation, the analysis of the changes in intracellular sodium activity under different conditions and the characteristics of overdrive excitation at different potential levels. The study should provide new information on a mechanism which is already shown to be responsible for the induction of fast rhythms in vitro and in vivo.
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