This project is designed to continue to provide a quantitative description of cardiac ionic currents and contractile activity and their modulation by neurohormones and drugs. Several investigations are planned that will provide further information about two important ionic channels in the heart: the calcium channel, a pathway for calcium ion influx during the action potential, and a calcium sensitive channel which carries a transient outward current. The project will combine the most recent procedures for pharmacological separation of ionic currents and for tissue preparation. Particular emphasis will be placed on studying channel properties that might influence the response of the channels to neurohormones or block of the channels by certain drugs.
A second aim of this project is to determine the mechanisms of action of an important group of drugs: dihydropyridine calcium channel blockers. Experiments are planned to determine the manneer in which membrane potential modulates blockade of calcium channels by, and binding to receptors of, these drugs. These results will be crucial to our understanding of the modes of action of these compounds in cardiac and other cells, and will help direct the use of these drugs towards specific tissues and/or towards the treatment of specific conduction disorders. Experiments will be carried out using voltage-clamp techniques in preparations obtained from cardiac Purkinje fibers and ventricular muscle. A conventional two microelectrode voltage clamp technique will be used to measure membrane currents in isolated segments of shortened Purkinje fiber cell bundles in some experiments. In other experiments, membrane currents will be measured in enzymatically-dispersed Purkinje fiber and ventricular muscle cells. In the latter experiments, a suction pipette will be used to measure whole cell and single channel currents. Optical techniques will be used to monitor contractile activity and drug binding.
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