Class III effects of dofetilide and arrhythmias are modulated by [K +] o in an in vitro model of simulated-ischemia and reperfusion in guinea-pig ventricular myocardium

Abstract

To evaluate class III effects of clinically relevant concentrations of dofetilide (5 and 10 nmol/l) and the effects of extracellular potassium [K +] o modulation of arrhythmias onset at the level of the “border zone,” we used a previously reported in vitro model whereby normoxic and ischemic/reperfused zones were studied. Guinea-pig right ventricular strips (driven at 1 Hz at 36.5 ± 0.5 °C) were superfused with Tyrode's solution in oxygenated (HCO 3 − 25 mmol/l, K + 4 mmol/l, pH 7.35 ± 0.05, glucose 5.5 mmol/l: normal zone) and ischemia-simulating conditions (HCO 3 − 9 mmol/l, pH 6.90 ± 0.05, no oxygen and no glucose: altered zone) having either [K +] o 4 ( n = 20), 8 ( n = 20) or 12 ( n = 20) mmol/l. Action potentials in normal and altered zones were recorded simultaneously during 30 min of simulated-ischemia and after 30 min of reperfusion with oxygenated Tyrode's solution. Each preparation served as control for successive phases of dofetilide studies (at 5 and 10 nmol/l) and action potential values were normalized to those present at the beginning of the experiment. During simulated-ischemia, the higher the [K +] o the worse were action potential changes, although full recovery was seen upon 30 min of reperfusion in all [K +] o groups. A high incidence of ischemia/reperfusion arrhythmias was observed in 4 and 12 mmol/l [K +] o groups as opposed to a low incidence of arrhythmias in 8 mmol/l [K +] o group. Dofetilide at 5 and 10 nmol/l with all [K +] o explored: (i) exhibited class III effects, (ii) was effective (or neutral) against ventricular arrhythmias during both simulated-ischemia and reperfusion, and (iii) did not globally increase the dispersion of action potential durations between normal and altered zones. Different arrhythmogenic mechanisms are involved in this model at different [K +] o with 8 mmol/l providing relative protection. Class III effects of dofetilide are evident in the normal zone when in the ischemic-like zone [K +] o ranges from 4 to 12 mmol/l. Thus dofetilide did not increase dispersion of repolarization and had either an antiarrhythmic or a neutral effect during ischemia/reperfusion.