EFFECT OF DISOPYRAMIDE ON POTASSIUM CURRENTS IN RABBIT VENTRICULAR MYOCYTES

The effects of disopyramide (1-30 mu M) on the 4-aminopyridine sensiti ve transient outward current (I-to), on the rapid component of the del ayed rectifier potassium current (I-Kr) and on the inward rectifier po tassium current (I-kl) were studied in single rabbit ventricular myocy tes at 35 degrees C by applying the whole-cell configuration of the pa tch clamp technique. Disopyramide signifiantly decreased the amplitude of I-to (from 1510 +/- 122 pA at control to 1015 +/- 21 pA after 30 m u M disopyramide at +50 mV; n = 5). This effect was not voltage-or use -dependent. Disopyramide (10 mu M) influenced neither the recovery fro m inactivation of I-to nor the steady-state inactivation curve. The dr ug dose dependently decreased the time constant of the fast component of the decay of I-to (tau(f) = 6.41 +/- 0.25 ms, n = 24 for control; a nd 2.20 +/- 0.38 ms, n = 5 after 30 mu M disopyramide at +50 mV). The fractional block caused by 30 mu M 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 mu M) 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 mu M. Our results are con sistent with an open-channel block of I-to by disopyramide, however, a weak, drug-induced increase of the rate of inactivation and a moderat e tonic block cannot be excluded, The amplitude of the outward tail cu t-rent attributed to I-Kr was depressed dose dependently by disopyrami de (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 o f 10 mu M disopyramide; n = 11). The estimated EC50 was 1.8 mu M. I-to is thus less sensitive to disopyramide than I-Kr, I-kl, was not influ enced significantly by disopyramide, even when applied in the highest tested concentration (30 mu M). It is concluded that in rabbit ventric ular myocytes disopyramide blocks not only I-Kr, but also I-to, both o f which may play an important role in the well established repolarizat ion lengthening and antiarrhythmic effects of the drug.