Shortening of the action potential and reduction of pacemaker activity by lidocaine, quinidine, and procainamide in sheep cardiac purkinje fibers. An effect on Na or K currents?

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Abstract
The ionic mechanism underlying the shortening of the action potential and the reduction in pacemaker activity by lidocaine, quinidine and procainamide in sheep cardiac Purkinje fibers was investigated using the 2-microelectrode voltage clamp technique. In the presenceof lidocaine (1.85-3.7 .times. 10-5 M), steady state currents were shifted outward over a broad range of potentials. Instantaneous currents (holding potential -40 mV) and steady state currents in 20 mM Cs-Tyrode were unaffected at potentials negative to -60 mV, the outward shift being restricted to potentials positive to this level. This outward shift of the current at the plateau level by lidocaine was not observed in the presence of a maximal dose of tetrodotoxin (TTX); in Na-free medium, the effect of lidocaine was totally suppressed. On the pacemaker current the major effect of lidocaine was to reduce the magnitude of the activation curve with no change in time constants or in the shape of the fully activated current-voltage relation. Quinidine and procainamide exerted similar effects on instantaneous currents. Quinidine affected the pacemaker in the same way as lidocaine, while procainamide had no effect on this current. Local anesthetics do not increase the K inward rectifier current and have no effect on inward background current at potentials negative to -60 mV; the shift in steady state currents at these levels is due to a change in pacemaker current. Because the lidocaine-sensitive pacemaker current does not reverse at the presumed equilibrium potential for K ions, and the effect of lidocaine in the presence of 1 mM Ba is similar to that in normal Tyrode, then the drug evidently inhibits a pacemaker current which is activated on hyperpolarization and mainly carried by Na ions. The results with TTX and in Na-free medium demonstrate that lidocaine inhibits a Na current, sensitive to TTX. The shortening of the action potential in sheep cardiac Purkinje fibers by local anesthetics is not due to an increase in outward current but can be explained by a block of an inward current, through the TTX-sensitive channel.