Concentration-dependent block of sodium current in guinea pig ventricular myocytes by a class III antiarrhythmic agent, MS-551.
Although MS-551 is classified as a class III antiarrhythmic agent (K+ channel blocker), its effect on the Na+ channel has not been fully characterized. We investigated the effect of MS-551 on the Na+ current (I(Na)) in isolated guinea pig ventricular myocytes. MS-551 blocked I(Na) in a concentration-dependent manner at a holding potential of -140 mV. The concentration-response curve revealed that the median inhibitory concentration (IC50) for the block of resting channel was 292 +/- 20 microM with a Hill coefficient of 1 (n = 11). Although MS-551, 300 microM, did not show a use-dependent block, it shifted the steady-state inactivation curve in a hyperpolarizing direction by 6.3 +/- 0.8 mV and delayed the recovery process from long depolarization. This delay was considered to be related to the drug unbinding and was expressed by a triple exponential function. The slowest component had a time constant of 409 +/- 35 ms, and the proportion of the amplitude of this component to the total current amplitude was 14 +/- 3% (n = 6). The IC50 for the inactivated Na+ channel was thus estimated to be 169 microM at maximum. These results suggest that MS-551 has a low affinity for both the resting and inactivated Na+ channel.
Suzuki
K
K
Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
Furukawa
T
T
Koyama
Y
Y
Sagawa
T
T
Nishimura
M
M
Yamanaka
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D011744:Pyrimidinones / Q000494:pharmacology*; D026941:Sodium Channel Blockers
D000889:Anti-Arrhythmia Agents; D011744:Pyrimidinones; D026941:Sodium Channel Blockers; C076259:nifekalant