HYPERKALAEMIA AND ACIDOSIS MODIFY HERG CHANNEL BIOPHYSICAL
PROPERTIES AND ANTAGONISE INHIBITION BY SOTALOL. B.D.
Walker*, H. Tie, C.B. Singleton, J.A. Bursill, K.R. Wyse, S.M. Valenzuela, S.N.
Breit, T.J. Campbell. Department
of Medicine, Victor Chang Cardiac Research Institute and Centre for Immunology,
St Vincent's Hospital, Darlinghurst, NSW. Background:
Hyperkalaemia and acidosis frequently accompany acute ischaemia and underlie
some of the associated electrophysiological changes. We examined the effects of hyperkalaemia and acidosis on the
human ether-a-go-go-related gene (HERG) channel, which encodes IKr in
the human heart. Methods and
results: A whole cell voltage-clamp
technique was used to study currents produced by stable transfection of HERG in
Chinese hamster ovary (CHO-K1) cells (standard solution: pH7.4; K4.8mM). Hyperkalaemia (pH7.4;K10) increased current
amplitude ~50% during a depolarising step, but reduced tail current amplitude
on repolarization to -60mV. This was
mainly due to slower inactivation kinetics and a +10mV shift in the
voltage-dependence of inactivation. These changes were more pronounced in
pH7.4;K20 solution and inhibition by sotalol (300mM) was 35% weaker than in
standard solution (p<0.01, n=7).
Mild acidosis (pH6.8;K4.8) did not affect current amplitude or gating,
but increased the rate of current deactivation two-fold and attenuated
inhibition by sotalol (300mM) by 18% (p<0.05,
n=9). Combined hyperkalaemia and
moderate acidosis (pH6.4;K10) decreased tail current amplitude by 60%, and
increased the rate of deactivation, without exerting major changes on
inactivation gating or kinetics. A 0.5s voltage ramp from +40 to -80mV (to
stimulate current during a cardiac action potential) demonstrated that a
pH6.4;K10 solution did not affect current in early repolarization, but reduced current > 50% during "phase
3 repolarization". Conclusions:
Hyperkalaemia and acidosis reduce outward current in late repolarization and
attenuate HERG channel inhibition by sotalol. This may explain a reduction in the antiarrhythmic
efficacy of sotalol in animal models of acute ischaemia.
