Project Details

Description

Our aims are to show that the interaction of all antiarrhythmic drugs with
the sodium channel in cardiac Purkinje fibers can be fully characterized
using a modification of the modulated receptor model. Specifically
association and dissociation rate constants thay may be voltage and/or
channel state dependent describe the affinity of drug to the sodium
channel. Using these rate constants it is possible to predict the voltage
dependence and frequency dependence of depression of Vmax by drugs that
block the sodium channel and one can explain the different cellular
electrophysiologic clinical electrocardiographic and therapeutic effects of
Type I antiarrhythmic drugs. Using Vmax as an indirect measure of sodium current we will use a double
microelectrode voltage clamp technique to perform standard inactivation and
reactivation experiments to determine the rate constants for binding and
unbinding to the sodium channel of the following drugs: lidocaine,
tocainide, quinidine, flecainide, amiodarone and propranolol. We will
determine whether the rate constants are voltage dependent as well as
channel state specific and use these rate constants in a computer model of
the action potential to simulate experiments designed to determine
frequency dependence of Vmax depression. We will compare the results of
the computer model simulations to our experimental results. In the
experiments we will elicit trains of action potentials of different cycle
lengths using our voltage clamp to control the height and duration of the
action potential and to control transmembrane voltage during phase 4. In
this way we can establish the relative importance of the action potential
upstroke and action potential plateau in determining how much drug binds to
the sodium channel and the role of transmembrane voltage in determining how
much drug unbinds from the sodium channel. We will determine the frequency dependence of conduction velocity in canine
Purkinje fibers and will determine the relative contributions of changes in
action potential duration and slowed reactivation of sodium channels in the
determination of the effective refractory period. Finally we will study
the effects on tonic and frequency dependent depression of Vmax using
combinations of the above drugs.
StatusFinished
Effective start/end date5/1/841/31/87

Funding

  • National Institutes of Health

ASJC

  • Medicine(all)

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