Cardiac arrhythmias induced by myocardial ischemia account for the majority of deaths related to coronary artery disease. The primary treatment for cardiac arrhythmias is antiarrhythmic drug therapy. Although it appears that many antiarrhythmic drugs exert their therapeutic effects by blocking sodium channels, the molecular and membrane basis for this action is not well understood. While there is evidence which indicates the presence of a specific receptor site for some tertiary amines, there is also considerable evidence to suggest that other drug types (e.g., neutral, anionic, or quaternary amines) may act by binding to different receptors, or by a non-specific mechanism of action. One of our primary aims is to rigorously test the hypothesis that """"""""all antiarrhythmic drugs which block sodium channels act by binding to a single common receptor site"""""""". This hypothesis will be tested by examining the effects of drug mixtures on cardiac sodium current in isolated guinea pig cardiac myocytes, and by mathematical modeling. Knowledge of the number and binding characteristics of antiarrhythmic drug receptors will be useful in understanding the molecular basis for antiarrhythmic drug action. A second major aim will be to investigate the effects of drug mixtures in order to determine which drug mixtures may produce clinically relevant interactions. Based upon knowledge of the effects of individual drugs, it should be possible to predict: 1) to what extent antiarrhythmic drug toxicity due to overdose can be reversed by administering a competitive antagonist (i.e., a second antiarrhythmic drug); 2) which drug mixtures will provide a more potent suppression of early extrasystoles than individual drugs themselves, with possible reduction of side effects, and 3) how active metabolites modify the electrophysiological effects of their parent antiarrhythmic drugs.
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