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 (iNCX) with the reversal potential of iNCX (ENCX) in the middle of the ramp voltage pulse employed. 2. Bi-directional iNCX 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 ENCX at -50 mV. 3. KB-R7943 (0.1 - 100 mirconM) concentration-dependently inhibited the current, which reversed near the calculated ENCX, indicating that the blocked current was iNCX. 4. The inhibition levels were not significantly different between outward and inward iNCX measured at 0 and -120 mV, respectively. IC50 of KB-R7943 was approximately 1 micronM for both directions of iNCX. 5. Under the bi-directional ionic conditions, only an outward or inward iNCX was induced by positive or negative 'half' ramp pulses, respectively, from the holding potential of -60 mV. KB-R7943 inhibited both direction of iNCX and the concentration-inhibition relations were superimposable to the ones obtained by 'full' ramp pulses. 6. These results indicate that KB-R7943 inhibits iNCX direction-independently under bi-directional conditions. This conclusion is different from that of our previous results obtained from iNCX under uni-directional ionic conditions, where KB-R7943 inhibited iNCX direction-dependently. The difference could be attributed to slow dissociation of the drug from the exchanger.
Kimura
J
J
Department of Pharmacology, Fukushima Medical University, School of Medicine, Fukushima 960-1295, Japan. jkimura@fmu.ac.jp
Watano
T
T
Kawahara
M
M
Sakai
E
E
Yatabe
J
J
D000818:Animals; D002469:Cell Separation; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D019831:Sodium-Calcium Exchanger; D013890:Thiourea