Objective: The frequency-dependent effects of MS-551 on the action potential duration (APD) and the underlying ionic mechanisms were investigated in comparison with those of E-4031. Methods: Whole-cell clamp techniques were used to study action potentials and ionic currents in enzymatically isolated rabbit ventricular myocytes. Results: The frequency-response obtained within the range of 0.1 to 3.3 Hz was different for MS-551 and E-4031. The APD prolongation by MS-551 (10 μM) was significant at 0.5-3.3 Hz, whereas that by E-4031 (1 μM) was significant at 0.1-1.0 Hz. The prolongation by MS-551 (10 μM) 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 μM) remained at the same level. Both MS-551 (10 μM) and E-4031 (1 μM) significantly decreased I(K), but showed no effects on the transient outward current (I(to)) and the inward rectifier K+ current (I(K1)). The development of the block on I(K) and the recovery from the block by MS-551 were voltage dependent. At a holding potential of -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 +10 mV, whereas at -75 mV, the intensity of the block progressively increased as the durations of depolarizing pulses were prolonged. The recovery from the block by MS-551 was absent at -50 mV, but occurred at -75 mV with a time constant of 577 ± 179 ms (n = 6). The development of the 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. Conclusions: These findings suggest that MS-551 produces frequency-dependent class In action, presumably due to the voltage-dependent binding and unbinding to the I(K) channels. The reverse frequency dependence of class III action by E-4031 cannot be explained by the effects on I(K).
Cheng, J., Kamiya, K., Kodama, I., & Toyama, J. (1996). Differential effects of MS-551 and E-4031 on action potentials and the delayed rectifier K+ current in rabbit ventricular myocytes. Cardiovascular Research, 31(6), 963–974. https://doi.org/10.1016/0008-6363(96)00049-1