Although the interaction between antiarrhythmic drugs and cardiac sodium channels has been intensively studied in vitro, the effects of these agents on sodium channel-dependent phenomena in the cardiac syncytium is less well-characterized. Factors known to alter the fast inward sodium current include drug concentration, stimulation frequency, transmembrane potential and factors in the extracellular milieu such as pH. The hypothesis we will test is that such information on the sodium channel blocking properties of antiarrhythmic drugs can be successfully exploited to study these agents in vivo. In preliminary studies, we have developed methods to measure, as a function of stimulation frequency and the extracellular environment, both direction-dependent conduction times and excitability in the intact heart. We ill use these methods, as well as HV time and QRS duration, as indices of the effect of drugs on sodium channel function in a series of animal preparations and in patients. The specific questions which we will address have arisen during both in vitro and patient studies. The in vitro studies focused on development and application of the Modulated Receptor Theory (MRT) of drug-ionic channel interactions. We will test several hypotheses based on the MRT: that certain drug combinations exert antagonistic effects on in vivo indices of sodium channel function, while others are synergistic; that MRT-based structure-activity relation studies can be used to identify agents with high potential for clinical utility; that alterations in the extracellular milieu (hyperkalemia, acidosis) affect drug action in a predictable fashion; that incorporation of the MRT into computer models of cardiac propagation results in faithful simulation of in vivo experimental data. The impetus for other studies we propose was the outcome of drug therapy in patients. Marked QRS widening by a new subclass of drugs (such as encainide and flecainide) has been associated with arrhythmia exacerbation. In preliminary studies, we have found that sodium salts reverse such QRS and HV increases in dogs; we will conduct studies to elucidate the mechanism and potential clinical applicability of this observation. We will also evaluate the possibility that drug metabolites may enhance or blunt the antiarrhythmic actions of parent drugs during chronic therapy. An actively collaborating group of basic and clinical scientists with overlapping interests have generated the preliminary data leading to this proposal and will continue to work together closely to address the questions posed in the proposal. This research will increase our understanding of the basic mechanisms of actions of antiarrhythmic drugs in the whole heart and has the potential to immediately improve care of patients with life-threatening arrhythmias.
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