Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block.
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.
Laboratory of Physiology, University of Oxford, Oxford, United Kingdom anthony.varghese@uwrf.edu.
Anthony
A
Varghese
Laboratory of Physiology, University of Oxford, Oxford, United Kingdom.
Anthony J
AJ
Spindler
Laboratory of Physiology, University of Oxford, Oxford, United Kingdom.
David
D
Paterson
Laboratory of Physiology, University of Oxford, Oxford, United Kingdom.
Denis
D
Noble
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003198:Computer Simulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology*; D008955:Models, Cardiovascular; D008962:Models, Theoretical; D009206:Myocardium; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects*; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D061567:Voltage-Gated Sodium Channel Blockers; D008012:Lidocaine
activation failure; conduction block; lidocaine; mathematical models