Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. An effect on steady state sodium currents?

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Abstract
The effects of lidocaine and quinidine on rabbit cardiac Purkinje fibers were compared at 37.degree. C, using action potential and voltage clamp measurements. At therapeutic concentrations (5 .mu.g/ml), lidocaine shortened the duration of the action potential while quinidine lengthened it. When membrane potential was held constant between -40 and -50 mV by the application of the 2-microelectrode voltage clamp, holding current consistently became more outward with lidocaine (+ 2.3 .+-. 0.7 nA, mean .+-. SEM [standard error of the mean], n = 5), but it either did not change or became more inward with quinidine (-2.1 .+-. 1.4 nA, n = 5). Both drugs reduced the outward tails generally associated with deactivation of the delayed rectifier current, ix. The depression of delayed rectification by quinidine (-68 .+-. 6%, n = 5) was greater than that produced by lidocaine (-12 .+-. 4%, n = 5), and can explain the observed prolongation of the action potential. To evaluate the possibility that lidocaine blocks steady-state Na channels, experiments were performed with tetrodotoxin (TTX), a specific blocker of Na channels in a variety of excitable membranes. TTX at concentrations of 0.1-5 .mu.M shortened the action potential, reducing its duration to 50% of control at 1.6 .mu.M. Voltage clamp experiments revealed a small TTX-sensitive component of steady-state current flowing at membrane potentials positive to -80 mV. In the presence of 10 .mu.M TTX, lidocaine failed to produce additional steady outward membrane current. Apparently, lidocaine and quinidine differ substantially in their modification of membrane channels, with quinidine having a strong effect on delayed rectification; a TTX-sensitive window current exists in the rabbit Purkinje fiber and helps maintain the action potential plateau; and the effect of lidocaine on the cardiac action potential results primarily from block to TTX-sensitive Na channels, rather than from an enhancement of potassium conductance.