Our primary objectives are the following. We will characterize the effects of standard and new antiarrhythmic drugs in terms of effects on three specific mechanisms for abnormal impulse generation: abnormal automaticity and early and late afterdepolarizations. We will attempt to identify drugs which are reasonably selective in terms of the changes they induce in the transmembrane potentials of cardiac Purkinje fibers. For these studies we will use standard microelectrode techniques and voltage-clamp. We also will develop means to record from the in situ heart the extracellular potential changes characteristic of the same three mechanisms for abnormal impulse generation. For these experiments we will use the canine heart and induce the arrhythmias either by surgical intervention, drug action or a combination of both. Finally, we will evaluate the specific mechanisms for antiarrhythmic action by administering the drugs with selective and characterized effects to dogs in which we have induced one of the three mechanisms for arrhythmia. We will monitor the extracellular potentials characteristic of the mechanism for impulse generation during the action of the drug to correlate antiarrhythmic efficacy with effect on the specific mechanism. By these methods we hope to be able to identify the actual mechanisms of antiarrhythmic action of drugs and also develop data that would permit us to use the response to specific drugs as a reliable indicator of the mechanism of arrhythmias of the human heart.
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