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While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na(+) channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2-6.67 Hz) and exposed to various concentrations (5 × 10(-6) to 500 × 10(-6) mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10(-4) mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10(-6) mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na(+) channel blockers.

Original publication




Journal article


Am J Physiol Heart Circ Physiol

Publication Date





H1753 - H1763


activation failure, conduction block, lidocaine, mathematical models, Action Potentials, Animals, Anti-Arrhythmia Agents, Computer Simulation, Guinea Pigs, Heart, Heart Ventricles, In Vitro Techniques, Lidocaine, Models, Cardiovascular, Models, Theoretical, Myocardium, Myocytes, Cardiac, Papillary Muscles, Voltage-Gated Sodium Channel Blockers