The effects of disopyramide (1-30 μM) on the 4-aminopyridine sensitive transient outward current (I(to)), on the rapid component of the delayed rectifier potassium current (I(Kr)) and on the inward rectifier potassium current (I(k1)) were studied in single rabbit ventricular myocytes at 35°C by applying the whole-cell configuration ofthe patch clamp technique. Disopyramide signifiantly decreased the amplitude of I(to) (from 1510 ± 122 pA at control to 1015 ± 21 pA after 30 μM disopyramide at +50 mV; n = 5). This effect was not voltage- or use-dependent. Disopyramide (10 μM) influenced neither the recovery from inactivation of I(to) nor the steady-state inactivation curve. The drug dose dependently decreased the time constant of the fast component of the decay of I(to) (τ(f) = 6.41 ± 0.25 ms, n = 24 for control; and 2.20 ± 0.38 ms, n = 5 after 30 μM disopyramide at +50 mV). The fractional block caused by 30 μM disopyramide as a function of time was well fitted by a single exponential function with time constant of 1.48 ± 0.18 ms (n = 5), most likely reflecting the binding kinetics of the drug to the open channel. The offset kinetics of the drug was estimated by using a double-pulse protocol and its time constant was 3.9 ± 0.5 ms. Disopyramide (30 μM) did not influence significantly the onset of inactivation measured at -20 mV. The estimated EC50 value for the I(to) block by disopyramide was 14.-1 μM. Our results are consistent with an open-channel block of I(to) by disopyramide, however, a weak, drug-induced increase of the rate of inactivation and a moderate tonic block cannot be excluded. The amplitude of the outward tail current attributed to I(Kr) was depressed dose dependently by disopyramide (after clamping the cells back to the holding potential from +30 mV, 139.5 ± 10.9 pA for control, and 30.7 ± 3.2 pA in the presence of 10 μM disopyramide; n = 11). The estimated EC50 was 1.8 μM. I(to) is thus less sensitive to disopyramide than I(Kr). I(K1) was not influenced significantly by disopyramide, even when applied in the highest tested concentration (30 μM). It is concluded that in rabbit ventricular myocytes disopyramide blocks not only I(Kr), but also I(to), both of which may play an important role in the well established repolarization lengthening and antiarrhythmic effects of the drug.
- Patch clamp
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