Direction-independent block of bi-directional Na+/Ca2+ exchange current by KB-R7943 in guinea-pig cardiac myocytes

1 We investigated the inhibitory effect of KB-R7943 on 'bi-directional' Na+/Ca2+ exchange current (i(NCX)) with the reversal potential of i(NCX) (E-NCX) in the middle of the ramp voltage pulse employed. 2 Bi-directional i(NCX) was recorded with 'full' ramp pulses given every 10 s from the holding potential of -60 mV over the voltage range between 30 and -150 mV under the ionic conditions of 140 mM [Na](o), 20 mM [Na](i), 1 mM [Ca](o) and 433 nM [Ca](i) with calculated E-NCX at -50 mV. 3 KB-R7943 (0.1-100 mu M) concentration-dependently inhibited the current, which reversed near the calculated E-NCX indicating that the blocked current was i(NCX). 4 The inhibition levels were not significantly different between outward and inward i(NCX) measured at 0 and -120 mV. respectively. IC50 of KB-R7943 was approximately 1 mu M for both directions of i(NCX). 5 Under the bi-directional ionic conditions, only an outward or inward i(NCX) was induced by positive or negative 'half' ramp pulses, respectively, from the holding potential of -60 mV. KB-R7943 inhibited both direction of i(NCX) and the concentration-inhibition relations were superimposable to the ones obtained by 'full' ramp pulses. 6 These results indicate that KB-R7943 inhibits i(NCX) direction-independently under bi-directional conditions. This conclusion is different from that of our previous results obtained from i(NCX) under uni-directional ionic conditions, where KB-R7943 inhibited i(NCX) direction-dependently. The difference could be attributed to slow dissociation of the drug from the exchanger.