DIFFERENTIAL-EFFECTS OF THE NEW CLASS-III ANTIARRHYTHMIC AGENTS ALMOKALANT, E-4031 AND D-SOTALOL, AND OF QUINIDINE, ON DELAYED RECTIFIER CURRENTS IN GUINEA-PIG VENTRICULAR MYOCYTES

Objectives: The effects of almokalant (4-[3-ethyl[3-(propylsulphinyl)propyl]-amino]-2-hydroxy-propoxy]-benzonitrile), E-4031 (1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulphonyl-amino-benzoyl)piperidine), d-sotalol, and quinidine were investigated on the delayed K+ rectifier current I(K). The aim of the study was to compare the drug action on the two components of this current. Methods: Membrane currents were measured in ventricular myocytes from guinea pig hearts with the whole cell voltage clamp technique. I(K) was activated during clamp steps from a holding potential of -40 mV to test potentials between -30 and +50 mV. The tail current I(tail) was measured upon stepping back to holding potential. Results: In control experiments, I(K) and I(tail) declined spontaneously ("run down"). With 300 ms long test pulses to +50 mV, only d-sotalol (10(-4) M) caused a significant further decrease in I(K), whereas all four agents significantly reduced I(tail) (almokalant 10(-6) M, E-4031 10(-7) M, quinidine 10(-5) M). When tested with 1 s long clamp steps at various potentials almokalant (3 x 10(-6) M), E-4031 (10(-6) M), quinidine (10(-5) M), and d-sotalol (10(-4) M) reduced I(K) in the potential range between -20 and +40 mV, yielding a bell shaped inward rectifying drug sensitive current. I(tail) was reduced by almokalant and E-4031 over the whole voltage range with saturation of block positive to +20 mV. Similar reductions with quinidine but not with d-sotalol were also significant. With rest pulses to +50 mV of increasing duration (25 ms-4000 ms), I(tail) developed with a faster time course than I(K) and therefore the ratio of I(tail)/I(K) declined with pulse duration. With almokalant and E-4031, this ratio became independent of test pulse duration. For 250 ms pulses, I(tail/I(K) was also significantly reduced by d-sotalol and quinidine. Conclusion: Inhibition of the rapidly activating inwardly rectifying component of I(K) is prominent with almokalant and E-4031 and less pronounced with d-sotalol and quinidine. Since inhibition of this component prolongs the cardiac action potential, it should contribute to the antiarrhythmic properties of the agents.