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

The Na+/Ca2+ exchanger plays a prominent role in regulating intracellular C a2+ levels in cardiac myocytes and can serve as both a Ca2+ influx and effl ux pathway. A novel inhibitor, KB-R7943, has been reported to selectively i nhibit 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 obtai ned from Xenopus laevis oocytes expressing the cloned cardiac Na+/Ca2+ exch anger NCX1.1, and outward, inward, and combined inward-outward currents wer e studied. KB-R7943 preferentially inhibited outward (i.e., reverse) Na+/Ca 2+ exchange currents. The inhibitory mechanism consists of direct effects o n the transport machinery of the exchanger, with additional influences on i onic regulatory properties. Competitive interactions between KB-R7943 and t he transported ions were not observed. The antiarrhythmic effects of KB-R79 43 were then evaluated in an ischemia-reperfusion model of cardiac injury i n Langendorff-perfused whole rabbit hearts using electrocardiography and me asurements of left ventricular pressure. When 3 muM KB-R7943 was applied fo r 10 min before a 30-min global ischemic period, ventricular arrhythmias (t achycardia and fibrillation) associated with both ischemia and reperfusion were almost completely suppressed. The observed electrophysiological profil e of KB-R7943 and its protective effects on ischemia-reperfusion-induced ve ntricular arrhythmias support the notion of a prominent role of Ca2+ entry via reverse Na+/Ca2+ exchange in this process.