Ibutilide, a new compound with potent class III antiarrhythmic activity, activates a slow inward Na+ current in...

Ibutilide, a class III antiarrhythmic compound under clinical development, was tested for specific activity on inward currents in guinea pig ventricular cells. Current clamp experiments showed a bell-shaped, dose-dependent effect of the compound on action potential duration and plateau height at concentrations beginning at 10(-9) M. In voltage clamp experiments in which the cells were bathed in K(+)-free solutions that contained external Na+0 and Ca++0, ibutilide, at 10(-8) M, increased a late inward current without affecting the fast inward Na+ current. The late inward current amplitudes, measured at 60 and 600 msec into a +20-m V step from -80 mV, were increased, respectively, from 0.73 +/- 0.07 to 1.1 +/- 0.06 nA, and from 0.02 +/- 0.02 to 0.15 +/- 0.03 nA, with a corresponding Kd of 2.3 x 10(-9) and 1.3 x 10(-9) M. However, if Na+0 was removed via appropriate ion substitution, the effect of ibutilide on the late inward current disappeared. On the other hand, when inward currents were maximized by the drug in Na+0 and Ca++0 containing external solution, removal of Na+0 reversibly removed a prominent late inward current which, when isolated from the L-type Ca++ current by current subtraction method, displayed a peak current potential of +30 mV and two decaying time constants of 38.2 +/- 3.8 and 200.8 +/- 43.3 msec at +20 mV. We concluded that ibutilide prolonged action potential duration through activation of a slow inward Na+ current. The identity of this current was discussed.