MOLECULAR MECHANISM OF TYPE I ANTIARRHYTHMIC ACTION

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.