Effects of Delayed Rectifier Current Blockade by E-4031 on Impulse Generation in Single Sinoatrial Nodal Myocytes of the Rabbit

The role of the delayed rectifier current (I sub K) in impulse generation was studied in single sinoatrial nodal myocytes of the rabbit. We used the class III antiarrhythmic drug E-4031, which blocks IK in rabbit ventricular myocytes. In single sinoatrial nodal cells, E-4031 (0.1 mu mol/L) significantly prolonged cycle length and action potential duration, depolarized maximum diastolic potential, and reduced both the upstroke velocity of the action potential and the diastolic depolarization rate. Half of the cells were arrested completely. At higher concentrations (1 and 10 mu mol/L), spontaneous activity ceased in all cells. Three ionic currents fundamental for pacemaking, ie, IK, the long-lasting inward calcium current (ICa,L), and the hyperpolarization-activated current (If), were studied by using the whole-cell and amphotericin-perforated patch technique. E-4031 blocked part of the outward current during depolarizing steps as well as the tail current upon subsequent repolarization (ITD) in a dose-dependent manner. E-4031 (10 mu mol/L) depressed ITD (88 plus minus 4%) (n equals 6), reduced peak ICa,L at 0 mV (29 plus minus 15%) (n equals 4), but did not affect If. Lower concentrations did not affect ICa,L. Additional use of 5 mu mol/L nifedipine demonstrated that ITD is carried in part by a calciumsensitive current. Interestingly, complete blockade of IK and ICa,L unmasked the presence of a background current component with a reversal potential of minus 32 plus minus 5.4 mV (n equals 8) and a conductance of 39.5 plus minus 5.6 pS/pF, which therefore can contribute both to the initial part of repolarization and to full diastolic depolarization. In conclusion, IK in conjunction with an inward background current plays an essential role in maintaining normal automaticity.(Circ Res. 1995;76:607-615.)