AIM: To investigate the effects of diltiazem, an L-type calcium channel blocker, and propafenone, a sodium channel blocker, on the inactivation and recovery kinetics of fKv1.4, a potassium channel that generates the cardiac transient outward potassium current. METHODS: The cRNA for fKv1.4ΔN, an N-terminal deleted mutant of the ferret Kv1.4 potassium channel, was injected into Xenopus oocytes to express the fKv1.4ΔN channel in these cells. Currents were recorded using a two electrode voltage clamp technique. RESULTS: Diltiazem (10 to 1000 μmol/L) inhibited the fKv1.4ΔN channel in a frequency-dependent, voltage-dependent, and concentration-dependent manner, suggesting an open channel block. The IC(50) was 241.04±23.06 μmol/L for the fKv1.4ΔN channel (at +50 mV), and propafenone (10 to 500 μmol/L) showed a similar effect (IC(50)=103.68±10.13 μmol/L). After application of diltiazem and propafenone, fKv1.4ΔN inactivation was bi-exponential, with a faster drug-induced inactivation and a slower C-type inactivation. Diltiazem increased the C-type inactivation rate and slowed recovery in fKv1.4ΔN channels. However, propafenone had no effect on either the slow inactivation time constant or the recovery. CONCLUSION: Diltiazem and propafenone accelerate the inactivation of the Kv1.4ΔN channel by binding to the open state of the channel. Unlike propafenone, diltiazem slows the recovery of the Kv1.4ΔN channel.
AIM: To investigate the effects of diltiazem, an L-type calcium channel blocker, and propafenone, a sodium channel blocker, on the inactivation and recovery kinetics of fKv1.4, a potassium channel that generates the cardiac transient outward potassium current. METHODS: The cRNA for fKv1.4ΔN, an N-terminal deleted mutant of the ferret Kv1.4 potassium channel, was injected into Xenopus oocytes to express the fKv1.4ΔN channel in these cells. Currents were recorded using a two electrode voltage clamp technique. RESULTS:Diltiazem (10 to 1000 μmol/L) inhibited the fKv1.4ΔN channel in a frequency-dependent, voltage-dependent, and concentration-dependent manner, suggesting an open channel block. The IC(50) was 241.04±23.06 μmol/L for the fKv1.4ΔN channel (at +50 mV), and propafenone (10 to 500 μmol/L) showed a similar effect (IC(50)=103.68±10.13 μmol/L). After application of diltiazem and propafenone, fKv1.4ΔN inactivation was bi-exponential, with a faster drug-induced inactivation and a slower C-type inactivation. Diltiazem increased the C-type inactivation rate and slowed recovery in fKv1.4ΔN channels. However, propafenone had no effect on either the slow inactivation time constant or the recovery. CONCLUSION:Diltiazem and propafenone accelerate the inactivation of the Kv1.4ΔN channel by binding to the open state of the channel. Unlike propafenone, diltiazem slows the recovery of the Kv1.4ΔN channel.
Authors: S Rolf; W Haverkamp; M Borggrefe; U Musshoff; L Eckardt; J Mergenthaler; D J Snyders; O Pongs; E J Speckmann; G Breithardt; M Madeja Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2000-07 Impact factor: 3.000