Flecainide and the electrophysiologic matrix: the effects of flecainide acetate on the determinants of cardiac excitability in sheep Purkinje fibers.
Flecainide was associated with excess mortality distributed virtually equally throughout the period of the Cardiac Arrhythmia Suppression Trial, suggesting the intersection of two events, drug effect and perhaps ischemia. Flecainide's effect on active properties has been studied extensively, but nothing is known of its effects on passive properties or on the balance among active and passive cellular properties that determines cardiac excitability. The multiple microelectrode method of intracellular current application and transmembrane voltage recording was used in sheep Purkinje fibers to determines strength- and charge-duration as well as constant current-voltage relationships and to estimate active properties, liminal length, and cable properties at a normal [K+]o and in a setting of hyperkalemia analogous to that of ischemia. A computer tracked in time the alterations in the active and passive properties relevant to excitability. Flecainide slightly decreased excitability at a normal [K+]o, primarily by depressing the sodium system with some contributory effect of passive properties. At high [K+]o, flecainide caused a frequency-dependent decrease in excitability and conduction, the latter best interpreted as a failure of the fiber to attain the liminal length requirements to produce a local action potential due primarily to an effect on sodium conductance. Together, the observations suggest that the action potential is the local phenomenon and that the propagated event is the sequential fulfillment of liminal length requirements. The data were interpreted in terms of the electrophysiologic matrix first proposed in detail in this Journal, which indicated that the electrophysiologic universe moved as a system in response to the drug and a change in [K+]o, the presumed antiarrhythmic and proarrhythmic electrophysiologic matrices for flecainide were quite similar, and the matrical configuration shared characteristics with the matrices of other drugs with known proarrhythmic potential.
Arnsdorf
M F
MF
Department of Medicine, University of Chicago, Illinois, USA. arnsdorf@medicine.bsd.uchicago.edu
Sawicki
G J
GJ
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology*; D005424:Flecainide / Q000494:pharmacology*; D006947:Hyperkalemia / Q000378:metabolism / Q000503:physiopathology; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000295:instrumentation; D011188:Potassium / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects / Q000503:physiopathology*; D012756:Sheep
D000889:Anti-Arrhythmia Agents; D005424:Flecainide; D011188:Potassium