Electrophysiologic actions and interactions between lysophosphatidylcholine and lidocaine in the nonsteady state: the match between multiphasic arrhythmogenic mechanisms and multiple drug effects in cardiac Purkinje fibers.
The effects and interactions between an arrhythmogenic intervention and an antiarrhythmic drug on active and passive cellular properties relevant to excitability were studied with multiple microelectrode methods and rapid online data analysis in cardiac Purkinje fibers. The arrhythmogenic intervention was superfusion with lysophosphatidylcholine (LPC), a metabolite that accumulates in the ischemic myocardium; and the antiarrhythmic drug was lidocaine. LPC (10-20 microM) initially increased excitability as manifested by a decreased threshold current and, when tested, by a downward shift in nonnormalized strength- and charge-duration curves. Normalized strength- and charge-duration curves suggested altered passive properties to be primarily responsible for increased excitability. Cable analysis showed LPC to increase significantly input resistance, membrane resistance, time constant and length constant; current-voltage relationships showed LPC to decrease chord and slope conductances over the subthreshold range. Lidocaine (4 micrograms/ml) decreased excitability both by depressing the sodium system and by directly countering the effects of LPC on conductance and related properties. LPC subsequently decreased excitability by depressing the sodium system and, in this phase, the further depressant effect of lidocaine on the sodium system predominated. Lidocaine could normalize action potentials that were prolonged or had two stable steady states after LPC, at times retarded LPC-induced inexcitability and could render the tissue inexcitable to intracellular point stimulation but not to extracellular stimulation. Interactions between the arrhythmogenic and pharmacologic interventions affected net excitability by altering the matrix of active and passive cellular properties in time. The results are relevant to the development of a rational matrical approach to understanding drug action and treating arrhythmias.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D006329:Heart Conduction System / Q000187:drug effects*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008839:Microelectrodes; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D012756:Sheep
D008244:Lysophosphatidylcholines; D008012:Lidocaine