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J Korean Med Sci
2009 Feb 01;241:84-91. doi: 10.3346/jkms.2009.24.1.84.
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Regulation of antiarrhythmic drug propafenone effects on the c-type Kv1.4 potassium channel by PHo and K+.
Wang Z
,
Wang S
,
Li J
,
Jiang X
,
Wang N
.
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The effects of the antiarrhythmic drug propafenone at c-type kv1.4 channels in Xenopus laevis oocytes were studied with the two-electrode voltage-clamp technique. Defolliculated oocytes (stage V-VI) were injected with transcribed cRNAs of ferret Kv1.4 Delta N channels. During recording, oocytes were continuously perfused with control solution or propafenone. Propafenone decreased the currents during voltage steps. The block was voltage-, use-, and concentration- dependent manners. The block was increased with positive going potentials. The voltage dependence of block could be fitted with the sum of monoexponential and a linear function. Propafenone accelerated the inactivate of current during the voltage step. The concentration of half-maximal block (IC(50)) was 121 microM/L. With high, normal, and low extracellular potassium concentrations, the changes of IC(50) value had no significant statistical differences. The block of propafenone was PH- dependent in high-, normal- and low- extracellular potassium concentrations. Acidification of the extracellular solution to PH 6.0 increased the IC(50) values to 463 microM/L, alkalization to PH 8.0 reduced it to 58 microM/L. The results suggest that propafenone blocks the Kv1.4 Delta N channel in the open state and give some hints for an intracellular site of action.
Fig. 1. Current-voltage relationship of fkv1.4ΔN currents under control condition (CTRL; filled symbols) and propafenone (open symbols; 100 µM/L PROP). Xenopus oocytes with all covering tissues. (A) original recordings, (B) current-voltage relationships of currents at the end of the voltage step. The symbols represent means±SEM of 14 experiments. Voltage steps were elicited from the holding potential of -80 mv to potential up to +50 mv. The currents were normalized to the respective maximal current amplitude under control condition (I current, U voltage).
Fig. 2. Voltage dependence of propafenone-induced block of fkv1.4ΔN currents. The concentration of propafenone were changed by 10 µM (diamonds) and 100 µM (squares) and 1,000 µM (triangles). Xenopus oocytes with all covering tissues. The graphical evaluation shows the fraction of inhibition of the fkv1.4ΔN currents in the potential range from -40 mv to +50 mv from 9 experiments.
Fig. 3. Frequency-dependent block of fKv1.4ΔN channel induced by propafenone. The currents were induced by a series of 500 ms depolarizing pulses from -80 to +50 mV with a frequency of 1 Hz for a period of 1 min in control solution (circles) and 100 µM propafenone (squares). The peak currents were normalized to the maximum peak current under control condition and plotted against pulse number.
Fig. 4. Effect of propafenone on fKv1.4ΔN recovery from C-type inactivation. The membrane was depolarized to +50 mV from the holding potential -80 mV for 5s (P1) followed by a second pulse (P2) to +50 mV for 1s with variable inter-pulse durations (inter-pulse potential was -80 mV). The inter-pulse durations were set as the following: 0.1 sec, 0.2 sec, 0.3 sec, 0.4 sec, 0.5 sec, 1 sec, 2 sec, 3 sec, 4 sec, 5 sec, 10 sec, and 20 sec. The peak currents induced by P2 were normalized to peak current induced by P1 and plotted against inter-pulse duration (A). (B) showed recovery time constants for control and 100 µM propafenone treated groups (n=5, p<0.05).
Fig. 5. graphical evaluation of the time constant (τ) of monoexponential fits. Xenopus oocytes with all covering tissues. Original recordings (A) and graphical evaluation of the time constant of monoexponential fits (B). The original recordings under control conditions and graphical evaluation of the time constant of monoexponential fits (A). The original recordings under control conditions and propafenone were obtained at voltage steps to +50 mv.
Fig. 6. The dose-responsiveness of propafenone of 1 µM/L up 1,000 µM/L on fkv1.4ΔN channels in 1 mM[K+]o (squares), 5 mM[K+] (diamonds) and 98 mM[K+] (triangles) (B). The dose-dependent inhibition of fKv1.4N was in (A). The recordings were graphical with voltage steps to +50 mv. The graphical evaluation slows the fraction of inhibition of the fkv1.4ΔN currents. All values represent means±SEM of the five experiments.
Fig. 7. Effects of the extracellular PH on the dose-responsiveness of propafenone on fkv1.4ΔN channel at extracellular potassium concentration of 98 mM[K+]0, 5 mM[K+]0, and 1 mM[K+]0. Xenopus oocytes with all covering tissues. The PH value of the extracellular solution was changed by PH 6 (triangles) and PH 7.4 (squares) and PH 8 (diamonds). Graphical evaluations under propafenone concentrations of 10 µM/L up to 1,000 µM/L. The graphical evaluation shows the fraction of inhibition of the fkv1.4ΔN currents. All values represents means±SEM of the five experiments each (I current, U voltage).
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