Characterization of concentration- and use-dependent effects of quinidine from conduction delay and declining conduction velocity in canine Purkinje fibers

The dynamic response of squared conduction velocity, θ², to repetitive stimulation in canine Purkinje fibers with quinidine was studied using a double-microelectrode technique. With stimulation, a frequency-dependent monoexponential increase in conduction delay (CD) and a decline in θ² were observed. The exponential rates and changes in steady-state CD and θ² were frequency- and concentration-dependent. The overall drug uptake rates describing blockade and the interpulse recovery interval were linearly related and steady-state values of θ² were linearly related to an exponential function of the stimulus intervals. Based on first-order binding, the frequency- and concentration-dependent properties of quinidine were characterized by the apparent binding and unbinding rates of 14.2 ± 5.7 x 10⁶ mol^-1 · s^-1 and 63 ± 12 s^-1 for activated and 14.8 ± 1.0 x 10² mol^-1 · s^-1 and 0.16 ± 0.03 s^-1 for resting states. The recovery time constant extracted from the pulse train interpulse interval was 5.8 ± 1.5 s compared with 5.1 ± 0.6 s determined from a posttrain test pulse protocol. This study demonstrates that the kinetics of drug action can be derived from measures of impulse propagation. This provides a basis for characterizing frequency-dependent properties of antiarrhythmic agents in vivo and suggests the plausibility of a quantitative assessment of drug binding and recovery rates in man.