Modulation of action potential duration by inhibition of the transient outward current in sheep cardiac Purkinje fibers.

In sheep cardiac Purkinje fibers concentration-dependent inhibition of transient outward current (ito) by 4-aminopyridine (4-AP, 3-1000 mumol/l) was recorded with the two-microelectrode voltage-clamp technique, and correlated effects on action potential duration measured at -70 mV (APD-70) were investigated. Half-maximal inhibition of ito-amplitude occurred at 15 mumol/l 4-AP. The drug exhibited no major effect on voltage-dependent control of inactivation but reduced the maximally available ito-current. At different activation frequencies (0.05 Hz, 0.25 Hz, 1 Hz) an equal amount of ito-current, measured as percentage of the respective control, was inhibited by 4-AP. The APD-70 was on the average increased by 4-AP (3-500 mumol/l) in a concentration-dependent manner up to 151% of control. The drug-induced prolongation, measured as percentage of the respective control, was independent of stimulation frequency (0.05 Hz, 0.25 Hz, 1 Hz). Prolongation of APD-70 was on the average more pronounced for short action potentials (APD-70 < 150 ms: 169% of reference) than for longer ones (APD-70 150-300 ms: prolongation to 117% of reference; 500 mumol/l 4-AP; 0.25 Hz stimulation rate). Few long control signals (APD-70 > 300 ms) were shortened by 4-AP. These results indicate that inhibition of ito-current by appropriate drugs will result in a reduction of inhomogeneity of action potential duration.