Characterization of Concentration- and Use-dependent Effects of Quinidine from Conduction Delay

The dynamic response of squared conduction velocity, 92, 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 92 were observed. The exponential rates and changes in steady-state CD and 92 were frequencyand concentration-dependent. The overall drug uptake rates describing blockade and the interpulse recovery interval were linearly related and steady-state values of 92 were linearly related to an exponential function of the stimulus intervals. Based on first-order binding, the frequencyand concentration-dependent properties of quinidine were characterized by the apparent binding and unbinding rates of 14.2±5.7 X 106 mol-' sand 63±12 s-' for activated and 14.8±1.0 X 102 mol' . *sand 0.16±0.03 so' 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 ofdrug 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.