ACTIONS AND MECHANISMS OF ACTION OF NOVEL ANALOGS OF SOTALOL ON GUINEA-PIG AND RABBIT VENTRICULAR CELLS

1 The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2 In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3 Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1-mu-M). Action potential prolongation by compound II was also unaffected in the presence of 10-mu-M tetrodotoxin. 4 Compound II (1-mu-M) did not influence I(K1) assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5 Compound II (1-mu-M) blocked time-dependent delayed rectifier potassium current (I(K)) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of I(K). 6 Submaximal concentrations of compound II were without effect on activation of I(K) with time at a membrane potential of + 40 mV, and no changes were detected in the time constants of the two components of I(K) decay over the range of potentials - 60 to 0 mV. Compound II (50 nM) appeared to cause a small shift in the activation of I(K) with membrane potential (an apparent shift of approximately 10 mV in the depolarizing direction at the mid-point of the curve). 7 Log dose-response curves for action potential prolongation and for blockade of I(K) by compound II were similar. The IC50 for compound II was approximately 30 nM. 8 It is concluded that this novel series of compounds prolongs action potential duration, and that in the case of compound II the evidence supports a potent selective effect on the time-dependent potassium current I(K), an effect which can account for this prolongation.