Abstract 2697: Role of Physiological Late Sodium Current in the Reverse-use Dependency of Potassium Current Inhibitors
Background: Reverse-use dependency (RUD) of an action potential prolongation by IKr inhibitors is proarrhythmic. We hypothesized that endogenous (physiological) late Na+ current (late INa) may contribute to the RUD of IKr inhibitors.
Methods: Female rabbit hearts were paced at 2.5, 2, 1.5, 1 and 0.5 Hz and exposed to either 20 nM E-4031 (a pure IKr blocker) or 10 μM D-sotalol (IKr and beta receptor blocker) in the absence and presence of 1 μM TTX (a relatively selective late INa inhibitor). Duration of the monophasic action potential (MAPD) recorded from the left ventricular epicardium was measured.
Results: In the absence of drug, MAPD90 increased from 150±2 to 203±5 ms as the rate of ventricular pacing was decreased from 2.5 to 0.5 Hz (open circles in the figure⇓) (n=14, p<0.01). Both E-4031 (20 nM, A) and D-sotalol (10 μM, B) increased MAPD90 at all ventricular rates (n=7, p<0.05– 0.01). At a heart rate of 0.5 Hz, episodes of torsade de pointes (TdP) were recorded in 6 out of 7 E-4031-treated hearts and in 5 out of 7 D-sotalol-treated hearts. TTX (1 μM) significantly attenuated the rate-dependent increases in MAPD90 at slower but not fast pacing rates in the continuous presence of either E-4031 or D-sotalol, respectively (n=7, p<0.01, see figure⇓). TTX (1 μM) abolished TdP in 5 of 6 hearts in the presence of 20 nM E-4031 and in 4 of 5 hearts in the presence of 10 μM D-sotalol.
Conclusion: Physiological late INa may play an important role in the RUD of IK inhibitors. Inhibition of late INa may diminish the rate-dependent prolongation of QT interval caused by either drugs or pathological conditions and therefore antagonize slow rate- or pause-triggered ventricular tachycardias.