The objective is to elucidate the interactive mechanisms of ion transport that regulate the electrochemical and electrophysiological properties of cardiac muscle. Rhythmic activity of cardiac muscle results from complex voltage and time dependent currents that are inextricably linked to fluctuations in intracellular and extracellular ion concentrations. The process of ascribing the components of membrane current to electrodiffusive mechanisms is now recognized as being complicated by transport mechanisms that are electrogenic (Na/K pump; Na/Ca exchange) and electroneutral (Na/H exchange; Na+K+2Cl co-transport). The functioning of these reversible, ion-coupled mechanisms depends on the membrane potential and the transmembrane ionic concentration gradients. Cultured embryonic chick heart cells will be studied by voltage-clamp and ion-selective microelectrode techniques in conjunction with the selected use of microspectrofluorometry and electron-probe x-ray spectrometry. Preparations having an experimentally induced increase in Na/K pump site density also will provide further insight into the Na/K pump and its interaction with ion-gradient coupled transport mechanisms.
The specific aims are designed to answer questions about transport kinetics and ligand affinities as well as the interaction between primary and secondary active transport processes. Measurement of intracellular ionic activities and compartmentation will provide the supportive data required to quantitate the electrical and chemical properties of these mechanisms and to relate these findings to the cardiac action potential. This research will facilitate a better understanding of the physiological properties of cardiac muscle as well as effects of clinically relevant cardioactive agents such as cardiac glycosides, Beta-agonists and loop diuretics.
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