Background: The small conductance Ca2+-activated K+ current (ISK) may be enhanced in ventricle as a result of heart failure, but whether ISK may be enhanced by [Ca2+]i-elevation, in non-failing ventricle, is unknown. Aim: To investigate the effects of an ISK blocker, ICA, on rabbit ventricular ion currents associated with [Ca2+]i elevation produced by stimulation of the Na+/Ca2+-exchanger current, INa/Ca. Methods: Ventricular myocytes were isolated from hearts excised from rabbits (anaesthetised with Na+-pentobarbital, 100 mg/kg I.V.). Ion currents and [Ca2+]i (by Fura-2) were recorded by whole-cell ruptured-patch clamp, at 35-37oC, before and after acute superfusion of ICA at 1 µM (~2 x IC50 for ISK) or 10 µM (potentially non-specific for ISK). [Ca2+]i was progressively, transiently (thus avoiding contracture) increased to supra-physiological levels, by repetitively stimulating reverse-mode INa/Ca, using voltage pulses (from -100 mV to +100 mV, 250 ms duration, 2 Hz frequency) whilst inhibiting ICaL (10 µM nifedipine), and sarcoplasmic reticular Ca2+ release (10 mM caffeine) and uptake (1 µM thapsigargin). Results: 1) In the absence of ICA, the INa/Ca stimulation protocol caused a stepwise, progressive, and marked increase in [Ca2+]i over the first ~20 voltage pulses, in each of 6 cells (from 2 rabbits) studied. The depolarising voltage change (to +100 mV) resulted in a peak [Ca2+]i of 1.17±0.33 µM (mean±SEM), associated with an outward current of +4.95±0.53 pA/pF, and the repolarising voltage change (to -100 mV) resulted in a peak [Ca2+]i of 0.67±0.09 µM and an inward current of ‑1.72±0.18 pA/pF. 2) In these 6 cells, ICA at 1 µM (started once the [Ca2+]i-elevation had plateaued) had no significant effect (P>0.05) on outward (+4.86±0.49 pA/pF) or inward (-1.73±0.18 pA/pF) current, nor on peak [Ca2+]i (1.16±0.33 µM at +100 mV, and 0.68±0.08 µM at -100 mV). However, subsequently-superfused (in 4 cells) NiCl2 (10 mM; to inhibit INa/Ca) significantly and markedly decreased, compared with the ICA 1 µM values, both outward current (from +4.92±0.76 to +2.44±1.16 pA/pF; a 50% decrease) and inward current (from -1.73±0.28 to -0.69±0.27 pA/pF; a 60% decrease), and [Ca2+]i (from 0.82±0.10 to 0.25±0.02 µM at +100 mV; a 70% decrease, and from 0.58±0.06 to 0.19±0.01 µM at -100 mV; a 67% decrease). 3) By contrast, ICA at 10 µM significantly reduced (vs control) both outward current (from +8.24±1.53 to +5.38±1.64 pA/pF; a 35% decrease) and inward current (from -2.86±0.33 to -1.45±0.55 pA/pF; a 49% decrease), as well as peak [Ca2+]i (significant at -100 mV: from 1.24±0.23 to 0.28±0.03 µM; a 77% decrease; 4 cells, 1 rabbit). Subsequently applied NiCl2 (n=3 cells) had no significant effect (vs ICA 10 µM) on outward or inward current, nor on [Ca2+]i. Conclusions: In non-failing ventricular myocytes, ISK (assessed as any response to 1 µM ICA) may not be activated by [Ca2+]i-elevation. Furthermore, ICA at ~20 x IC50 for ISK, may inhibit INa/Ca.