The general goal of this project is to understand the factors which control the force of cardiac muscle contraction. More specifically the goals are to elucidate mechanisms of excitation-contraction (E-C) coupling and to gain insight into the interrelationships involved in the regulation of intracellular Ca, Na, pH and K. The relative roles of Ca influx and SR Ca release in the beat to beat control of cardiac contractility is an important and controversial question. The planned studies will provide direct information bearing on this issue. Experiments will be done using double barreled Ca selective microelectrodes to measure transient depletions of Cao which occur during individual beats reflecting phasic Ca influx and cumulative depletions of Cao which occur over several beats reflecting changes in Ca content. Studies of the regulation, interaction and compartmentalization of intracellular Ca, Na and H ions will also be undertaken using ion selective microelectrodes to continuously and directly monitor the intracellular activities of these ions (in normal, physiologically altered and ischemic conditions). Aspects of how these cations interact at sarcolemmal sites will be studied in isolated cardiac sarcolemmal vesicles. These will allow assessment of sidedness, symmetry, Na-Ca exchange, the Na-H exchange and Ca binding in the sarcolemmal vesicles and the role these properties may have in the control of cardiac contractility. Biophysical models will be developed to describe how Ca, Na and H interact with sarcolemma bearing fixed negative charges and to describe the effects of electrodiffusive forces acting on Ca as it converges on a Ca channel. There is also much insight to be gained in technically simple experiments taking advantage of pharmacological agents, physiological manipulations and cardiac tissues with apparently differing E-C coupling mechanisms. The results of the studies planned should increase our understanding of the regulation of basic cardiac muscle function in normal as well as pharmacologically and pathologically altered states.
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