Inhibition of Na⁺/Ca²⁺ exchange by KB-R7943: transport mode selectivity and antiarrhythmic consequences

Abstract

The Na+/Ca2+ exchanger plays a prominent role in regulating intracellular Ca2+ levels in cardiac myocytes and can serve as both a Ca2+ influx and efflux pathway. A novel inhibitor, KB-R7943, has been reported to selectively inhibit the reverse mode (i.e., Ca2+ entry) of Na+/Ca2+ exchange transport, although many aspects of its inhibitory properties remain controversial. We evaluated the inhibitory effects of KB-R7943 on Na+/Ca2+ exchange currents using the giant excised patch-clamp technique. Membrane patches were obtained from Xenopus laevis oocytes expressing the cloned cardiac Na+/Ca2+ exchanger NCX1.1, and outward, inward, and combined inward-outward currents were studied. KB-R7943 preferentially inhibited outward (i.e., reverse) Na+/Ca2+ exchange currents. The inhibitory mechanism consists of direct effects on the transport machinery of the exchanger, with additional influences on ionic regulatory properties. Competitive interactions between KB-R7943 and the transported ions were not observed. The antiarrhythmic effects of KB-R7943 were then evaluated in an ischemia-reperfusion model of cardiac injury in Langendorff-perfused whole rabbit hearts using electrocardiography and measurements of left ventricular pressure. When 3 microM KB-R7943 was applied for 10 min before a 30-min global ischemic period, ventricular arrhythmias (tachycardia and fibrillation) associated with both ischemia and reperfusion were almost completely suppressed. The observed electrophysiological profile of KB-R7943 and its protective effects on ischemia-reperfusion-induced ventricular arrhythmias support the notion of a prominent role of Ca2+ entry via reverse Na+/Ca2+ exchange in this process.

Systems analysis of digoxin kinetics and inotropic response in the rat heart: effects of calcium and KB-R7943

“…4 ] i dependency of e T ). This is consistent with previous results showing that KBR preferentially blocks the Ca 2ϩ influx (reverse) mode of the cardiac NCX rather than the extrusion (forward) mode (2,10,25,39,45) and that KBR inhibits Ca 2ϩ influx through NCX under Na ϩ -loaded conditions in rat myocardium (18,38,41,49). Furthermore, it has been shown that Ca 2ϩ influx (via reversal of NCX) is essential for digitalisinduced potentiation of cardiac basal energy expenditure (15).…”

Effects of SEA0400 on Mutant NCX1.1 Na+-Ca2+Exchangers with Altered Ionic Regulation

“…Using a variety of techniques, KB-R7943 was also found to exhibit transport mode selectivity, whereby inhibition of the reverse transport mode was favored (Iwamoto et al, 1996;Watano et al, 1996;Elias et al, 2001; but see Kimura et al, 1999). The site of action of KB-R7943 remains unknown, although amino acid residues (particularly Gly833) within the ␣-2 repeat region of the exchanger have been reported to markedly affect drug sensitivity (Iwamoto et al, 2001).…”

The Exchanger Inhibitory Peptide Region-Dependent Inhibition of Na+/Ca2+Exchange by SN-6 [2-[4-(4-Nitrobenzyloxy)benzyl]thiazolidine-4-carboxylic Acid Ethyl Ester], a Novel Benzyloxyphenyl Derivative

“…influx) by NCX much more effectively than the forward mode (Iwamoto et al, 1996(Iwamoto et al, , 2004Elias et al, 2001). In addition, KB-R7943 is 3-fold more effective on NCX3 than on NCX1 and NCX2 , whereas SEA0400 predominantly blocks NCX1 compared with NCX2 and NCX3 (Iwamoto et al, 2004).…”