DIFFERENTIAL-EFFECTS OF MS-551 AND E-4031 ON ACTION-POTENTIALS AND THE DELAYED RECTIFIER K+ CURRENT IN RABBIT VENTRICULAR MYOCYTES

Objective: The frequency-dependent effects of MS-551 on the action pot ential duration (APD) and the underlying ionic mechanisms were investi gated in comparison with those of E-4031. Methods: Whole-cell clamp te chniques were used to study action potentials and ionic currents in en zymatically isolated rabbit ventricular myocytes, Results: The frequen cy-response obtained within the range of 0.1 to 3.3 Hz was different f or MS-551 and E-4031, The APD prolongation by MS-551 (10 mu M) was sig nificant at 0.5-3.3 Hz, whereas that by E-4031 (1 mu M) was significan t at 0.1-1.0 Hz, The prolongation by MS-551 (10 mu M) of APD of a test action potential, which was preceded by a train of 1.0 Hz stimulation , decreased progressively as the rest duration increased, whereas that by E-4031 (1 mu M) remained at the same level. Both MS-551 (10 mu M) and E-4031 (1 mu M) significantly decreased I-K, but showed no effects on the transient outward current (I-to) and the inward rectifier K+ c urrent(I-K1). The development of the block on I-K and the recovery fro m the block by MS-551 were voltage dependent, At a holding potential o f -50 mV, MS-551 reduced the tail current to a similar extent (21-34%, n=6) across all the tested durations of the depolarizing pulses to +1 0 mV, whereas at -75 mV, the intensity of the block progressively incr eased as the durations of depolarizing pulses were prolonged. The reco very from the block by MS-551 was absent at -50 mV, but occurred at -7 5 mV with a time constant of 577+/-179 ms (n=6). The development of th e block on I-K by E-4031 was voltage and time independent. No recovery from the block was observed for E-4031 at either -50 or -75 mV, Concl usions: These findings suggest that MS-551 produces frequency-dependen t class III action, presumably due to the voltage-dependent binding an d unbinding to the I-K channels, The reverse frequency dependence of c lass III action by E-4031 cannot be explained by the effects on I-K.