Chen H , Zhang D , Hua Ren J , Ping Chao S .

	Figure 1. Effects of verapamil (A) and diltiazem (B) on fKv1.4ΔN channels expressed in Xenopus oocytes. Representative curves are shown for 5-second depolarizing pulses from -90 mV to voltages between –100 and +50 mV in steps of 10 mV. Upper panels: traces recorded under control conditions. Middle panels: current traces obtained in the presence of 250 μmol/L verapamil or 250 μmol/L diltiazem. The peak currents in the presence of verapamil and diltiazem were poorly resolved from the capacitance transient on this time scale. Bottom panels: effects of 250 μmol/L verapamil and 250 μmol/L diltiazem on the peak current-voltage (I-V) relationships. Currents were normalized to the peak current at +50 mV under control conditions. The IDrug/IControl ratio was plotted as a function of the membrane potential. Data are shown as mean ± SEM (n = 5).
	Figure 2. Concentration-response relationships for the inhibition of the fKv1.4ΔN currents by verapamil (A) and diltiazem (B). Upper panels: Representative current traces were elicited in the absence and presence of increasing concentrations of verapamil (A) and diltiazem (B). Currents were recorded by depolarizing pulses to +50 mV from a holding potential of –90 mV. Lower panels: The peak currents were normalized the maximum peak current under control conditions and plotted against verapamil (A) and diltiazem (B) concentrations. The curves were derived by fitting data to the Hill equation: f = KD/ (KD + D), where f is fractional current, KD is the apparent dissociation constant, and D is the drug concentration. Symbols and error bar are mean ± SEM (n = 5).
	Figure 3. Use-dependent block of fKv1.4ΔN currents by verapamil (A) and diltiazem (B). Upper panels: Sixty repetitive depolarizing pulses from –90 to +50 mV for 500 ms each were applied in the absence and in the presence of verapamil (A) and diltiazem (B). Lower panels: Each peak current was normalized to the peak current at the first pulse under control conditions and then plotted against the number of pulses. Data are shown as mean ± SEM (n = 5).
	Figure 4. Effects of verapamil (A) and diltiazem (B) on the kinetics of the fKv1.4ΔN channel recovery from steady inactivation. The degree of recovery was measured by following a standard variable interval gapped pulse protocol. An initial 5-second pulse (P1) from –90 to +50 mV was followed by a second pulse (P2) to +50 mV after an interval of between 0.1 and 20 sec. The ratio of the peak current elicited by the P1 and P2 pulses (P2/P1) is plotted as a function of the various interpulse intervals. The continuous line represents the fit of the data to the equation: f = 1 - A*exp(–τ/t), where t is duration (in sec), τ is the time constant, A is the amplitude of the current. Data were normalized between 0 and 1 presented with intervals on a log scale. Data are shown as mean ± SEM (n = 5).
	Figure 5. Effects of verapamil (A) and diltiazem (B) on the activation of the fKv1.4ΔN currents. Current traces were obtained by applying 80 ms pulses to potentials ranging from –100 to +50 mV and were followed by tail currents upon repolarization to –40 mV in the absence (upper panels) and in the presence of 250 μmol/L verapamil and 250 μmol/L diltiazem (middle panels). Bottom panels: steady-state activation relationships. The peak currents (measured at +50 mV) are plotted as a function of the holding potential. Continuous lines represent the fit of the data to a Boltzmann equation: f = 1/{1 + exp*[(V – V1/2)/k)]}, where V represents the test potential, V1/2 is the mid-point of activation, and k is the slope factor. Average data are shown as mean ± SEM (n = 5).
	Figure 6. Changes in the inactivation kinetics of fKv1.4ΔN currents by verapamil (A) and diltiazem (B). Upper panels: Steady-state inactivation was studied using a two-pulse voltage protocol. Currents were measured at +50 mV, and the 5-sec pre-pulses to potential varied from –100 to +50 mV in steps of 10 mV. The curves for steady-state inactivation were fitted with the Boltzmann equation: f = 1/{1 + exp*[(V – V1/2)/k)]}. Where V represents the test potential, V1/2 is the mid-point of inactivation, and k is the slope factor. Lower panels: time constant of inhibition as a function of the drug concentration. Time constants (τblock) were estimated from a single or double exponential fits to the tracings shown in Figure 2. The apparent rate constants for association (k+1) and dissociation (k–1) were obtained from the equation: 1/τblock = k+1[d] + k–1. Data are shown as mean ± SEM (n = 5).

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