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

Abstract

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]0, 20 mM [Na](i), 1 mM [Ca]0 and 433 nM [Ca](i) with calculated E(NCX) at -50 mV. 3. KB-R7943 (0.1-100 μM) 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 μM 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 super-imposable 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.