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

Abstract

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 frequency-and 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 frequency-and concentration-dependent properties of quinidine were characterized by the apparent binding and unbinding rates of 14.2±5.7 X 106 mol-' s-and 63±12 s-' for activated and 14.8±1.0 X 102 mol' . *s-and 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.

Direct quantification of apparent binding indices from quinidine-induced in vivo conduction delay in canine myocardium.

“…Hondeghem and Katzung (2) obtained a value of ka that was larger (26.0 X 106 M-1 s-'), however, which could be accounted for by the shorter 0.3-ms activated state uptake time applied in the latter calculations of ka. Our estimated unbinding rate from the activated channel la = 81 s51, was also on the same order as those derived previously from Purkinje fibers (5) and that predicted by Hondeghem and Katzung (2).…”

“…The estimation of fractional QUIN-induced Na' channel block from changes in conduction is based on assumptions previously applied and validated by Packer et al (5) in vitro and by Nattel and coworkers in vivo (14,15). It was assumed that 02 was a linear function of gN.…”

“…The normalized slope expressions of CD(N) were used as markers of drug effect under both steadystate and dynamic conditions. From these, the kinetics of accumulation of and recovery from block were described in terms of a special application of a three-state model of drug binding (5,20). For this approach, overall drug block is viewed as an alternating sequence of three exponentials describing drug uptake during active, inactive, and resting channel states of duration ta, ti, and tr, with descriptive drug uptake rates of Xa, Xi, and Xr, respectively.…”

“…The analytic methods of the parameter estimation procedures and their specific implementation in the quantification of QUIN-induced CD have been described previously in greater detail (5).…”

“…Although the exact relationship between Na+ conductance (gNa) and conduction velocity (0) is uncertain, several investigators have demonstrated a linear relationship between drug-induced changes in 02 and Vm. in guinea pig papillary muscle (4) and canine Purkinje fibers (5). Furthermore, assuming a linear relationship between gNa and 02, Nattel (6) In contrast to the extensive literature detailing these use-dependent conduction changes in vitro, the analysis ofuse dependence in vivo has been largely qualitative.…”