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 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 microM) was significant at 0.5-3.3 Hz, whereas that by E-4031 (1 microM) was significant at 0.1-1.0 Hz. The prolongation by MS-551 (10 microM) 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 microM) remained at the same level. Both MS-551 (10 microM) and E-4031 (1 microM) significantly decreased IK, but showed no effects on the transient outward current (Ito) and the inward rectifier K+ current (IKl). The development of the block on IK 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 IK 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 III action, presumably due to the voltage-dependent binding and unbinding to the IK channels. The reverse frequency dependence of class III action by E-4031 cannot be explained by the effects on IK.
Cheng
J
J
Department of Circulation, Nagoya University, Japan.
Kamiya
K
K
Kodama
I
I
Toyama
J
J
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005260:Female; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects*
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011725:Pyridines; D011744:Pyrimidinones; C063968:E 4031; C076259:nifekalant; D000254:Sodium-Potassium-Exchanging ATPase