Properties of the bursting Na channel in the presence of DPI 201-106 in guinea-pig ventricular myocytes

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Abstract
Single Na channel currents were measured in cellattached patches of guinea-pig ventricular myocytes in the presence of the S-enantiomer of DPI 201-106. DPI changes the kinetic pattern of channel activity from short living openings at the beginning of a depolarizing pulse (voltageindependent mean open time about 0.4 ms between −60 and −20 mV), into longlasting bursts of openings. The single channel current-voltage relation can be approximated by a straight line with a single channel conductance of 15 pS, which is the same as in the absence of DPI, and a reversal potential near the estimated Na equilibrium potential (+ 74 mV). The ensemble averaged Na current shows a fast peak of inward current, which partially decays within less than 10 ms, but which shows a large component which decays very slowly with a time constant of the order of 1s (1.31±0.6 s at −30 mV, 19 measurements in 12 cell-attached patches). The slowly decaying component activates with a half-maximum potential at −55.4±2.3 mV and a slope parameter s of 4.9±1.9 mV. The half-maximum potential of the steady-state inactivation is −115.6±1.8 mV, and the slope parameter is 9.1±1.5 mV. The open time distribution can be fitted by a single exponential only at potentials negative to −40 mV. The time constant is 1.3±0.14 ms at −50 mV (7 patches). At more positive potentials a slower second component is present (14.4±7.1 ms at −30mV, 7 patches), in addition to a fast component with a time constant between 2 and 3 ms (2.2±1.9 ms at −30 mV, 7 patches). The closed time distribution contains two exponential components. The time constant of the fast component decreases from about 1.3 ms at −70 mV to 0.3 ms at −20 mV (0.3±0.17 ms at −30 mV, 10 patches). The time constant of the second component decreases from about 4.0 ms at −70 mV to 1.5 ms at −20 mV (2.2±1.8 ms at −30 mV, 10 patches). At potentials positive to −50 mV also a small very slow component is present (8.8±5.6 ms at −30 mV). The contribution of the slow component to the closed time distribution increases for stronger depolarizations from 2.2±2.1% at −40 mV to 64±22% at −20 mV. The contribution of short closings to the total number of closings is increased from 51±4% at −70 mV to 83±12% at −20 mV. Openings occur clearly in bursts and the burst duration shows a very good correlation with the time constant of the decay of the ensemble average current in a large number of different experimental conditions. The channels are blocked by application of TTX. With 10 and 30 μM TTX in the patch pipette (1 s pacing interval) the probability of the channel being open is decreased by about 90%. The long mean open time is significantly reduced when TTX is present in the patch pipette (5.7±2.6 ms at −30 mV with 5–30 μM TTX, 4 patches,n=11). No significant differences are obtained for both closed times (τc1 = 0.26±0.07 ms, τc2 = 1.9±0.7 ms, 4 patches,n=9). The steady-state inactivation is not significantly changed in the presence of TTX (VH=−112±2.9 mV, s=9.0±2.8 mV). The open state probability of the bursting Na channel is also reduced by more than 80% when 200 μM Cd is present in the pipette solution (all mean ±SD).

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