Role of Ca2+ -activated CI- current in ventricular action potentials of sheep during adrenoceptor stimulation

Abstract

Adrenoceptor stimulation enhances repolarising and depolarising membrane currents to different extents in cardiac myocytes. We investigated the opposing effects of the repolarising Ca2+-activated Cl- current (ICl(Ca)) and depolarising L-type Ca2+ current (ICa,L) on the action potential configuration of sheep ventricular myocytes stimulated with noradrenaline. Whole-cell current-clamp recordings revealed that noradrenaline accelerated and prolonged phase-1 repolarisation. We define the minimal potential at the end of phase-1 repolarisation as 'notch level'. Noradrenaline (1 μM) caused the notch level to fall from 14±2.6 to 7.8±2.8 mV (n=24), but left action potential duration, resting membrane potential or action potential amplitude unaffected. Whole-cell voltage-clamp recordings showed that 1 μM noradrenaline increased both ICa,L and ICl(Ca), but it had no significant effect on the principal K+ currents. Blockage of ICl(Ca) by 0.5 mM 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (DIDS) in both the absence and the presence of noradrenaline abolished phase-1 repolarisation. In the presence of noradrenaline, DIDS caused elevation of the plateau phase amplitude and an increase in the action potential duration. In conclusion, elevation of the plateau phase amplitude and action potential prolongation associated with an increased ICa,L upon adrenoceptor stimulation is prevented by an increased ICl(Ca) in sheep ventricular myocytes.