Effects of tocainide and lidocaine on the transmembrane action potentials as related to external potassium and calcium concentrations in guinea-pig papillary muscles

Abstract

Effects of lidocaine and tocainide on transmembrane potentials were studied in isolated guineapig papillary muscles, superfused with modified Tyrode's solution containing either 5.4, 2.7, 10.0 or 8.1 mmol/l potassium concentration, [K]₀. The last solution applied contained either 1.8 (normal [Ca]₀) or 7.2 mmol/l [Ca]₀) (high [Ca]₀). The concentrations of lidocaine and tocainide used were 18.5, 36.9 and 73.9 μmol/l and 43.7, 87.5 and 174.9 μmol/l in 5.4 mmol/l [K]₀ solution and 36.9 and 87.5 μmol/l in the other solutions, respectively. At the driving rate of 1 Hz in 5.4 mmol/l [K]₀ solution, both drugs produced dosedependently a reduction of maximum rate of rise of action potential (\(\dot V_{\max } \)), together with a prolongation of the relative refractory period. \(\dot V_{\max } \) decreased progressively as the driving rate was increased from 1 Hz (for lidocaine) and from 0.25 Hz (for tocainide) to 5 Hz. This action was accentuated dose-depently. A slow component (time constant τ=195–232 ms for lidocaine, 281–303 ms for tocainide) and slower component (τ=2.1–3.8 s for tocainide) of the recovery (reactivation) of \(\dot V_{\max } \) were observed in premature responses at 0.25 Hz and in the first response after interruption of the basic driving rate at 1 Hz. All these effects were accentuated with rising [K]₀ and attenuated in the high [Ca]₀ solution. Both drugs abbreviated the action potential duration at 50% (APD₅₀) and 90% (APD₉₀) levels at 5.4, 8.1 and 10.0 mmol/l [K]₀ but not at 2.7 mmol/l [K]₀ nor a high [Ca]₀ at 1 Hz. These [K]₀-dependent effects of lidocaine on \(\dot V_{\max } \) were successfully simulated by the model proposed by Hondeghem and Katzung (1977), with a slight change in parameter values. The mode of interaction of lidocaine with sodium channels in the open, closed and rested states was deduced from these results.