The cardiac transient outward potassium current: a pulse chemistry model of frequency-dependent properties. Liu, Lieju, V. I. Krinsky, A. O. Grant, and C. Frank Starmer. Departments of Medicine (Cardiology) and Computer Science, Duke University Medical Center, Durham N.C. 27710 and Institute of Theoretical and Experimental Biophysics, Moscow Region, Pushchino, Russia 142292
APStracts 2:0327H, 1995.
Recent voltage clamp studies of isolated myocytes have demonstrated widespread occurrence of a transient outward current carried by potassium ions. In the canine ventricle, this current is well developed in epicardial but not endocardial cells. The resultant spatial dispersion of refractoriness is potentially proarrhythmic and may be amplified by channel blockade. The inactivation and recovery time constants of this channel are in excess of several hundred milliseconds and consequently channel availability is frequency -dependent at physiologic stimulation rates. When the time constants associated with transitions between different channel conformations are rapid relative to drug-binding kinetics, the interaction between drugs and an ion channel can be approximated by a sequence of first -order reactions where binding occurs in pulses in response to pulse -train stimulation (pulse chemistry). When channel conformation transition time constants do not meet this constraint, then analytical characterizations of the drug-channel interaction must be modified to reflect the channel time-dependent properties. Here we report that the rate and steady-state amount of frequency-dependent inactivation of Ito is consistent with a generalization of the channel blockade model: channel availability is reduced in a pulsatile, exponential pattern as the stimulation frequency is increased and the rate of reduction is a linear function of the pulse-train depolarizing and recovery intervals. Ito was reduced in the presence of quinidine. After accounting for the use-dependent availability of Ito channels, we found little evidence of an additional use-dependent component of block after exposure to quinidine, suggesting quinidine reacts with both opened and closed Ito channels as though the binding site is continuously accessible. The model provides a useful tool for assessing drug-channel interactions where the reaction cannot be continuously monitored. 

Received 31 August 1992; accepted in final form 11 July 1995.
APS Manuscript Number H772-2.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 10 August 1995.