Funds are requested to continue support of a study of the specificity and mechanism of action of a variety of Na+, Ca++ and K+ -antagonists in enzymatically dispersed single myocytes from frog and guinea-pig hearts. In comparison to multicellular cardiac preparations, isolated single cells offer a number of important advantages for quantitative voltage-clamp and pharmacological studies: (i) the ability to study possible mechanisms of pharmacological modulation of ion channel function both at the level of whole-cell ionic currents as well as single channel currents, and (ii) the ability to carefully assess the specificity of pharmacological agents on each component of ionic current under conditions in which contamination by other currents is minimal. Considerable recent progress has been made in understanding the interactions of several organic Ca++ channel antagonists with Ca++ and K+ channels in single frog atrial myocytes. We propose to continue these experiments in isolated single guinea-pig myocytes to include an analysis of the mechanism of action and specificity of several Na+ and K+ channel antagonists. Since many of the compounds to be studied are important therapeutic agents used clinically to treat a variety of cardiovascular conditions, the proposed experiments will provide new information with regard to the cellular actions of these compounds. This information will contribute to a better understanding of cardiac arrhythmias in general and may lead to the development of newer and more effective antiarrhythmic agents.
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