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

• Published in: American journal of physiology. Heart and circulatory physiology 2001-09, Vol.281 (3), p.H1334-H1345
• Main Authors: Elias, Chadwick L, Lukas, Anton, Shurraw, Sabin, Scott, Jason, Omelchenko, Alexander, Gross, Gil J, Hnatowich, Mark, Hryshko, Larry V
• Format: Article
• Language: English
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - complications; Arrhythmias, Cardiac - physiopathology; Arrhythmias, Cardiac - prevention & control; Binding, Competitive - drug effects; Binding, Competitive - physiology; Calcium - metabolism; Cells, Cultured; Dose-Response Relationship, Drug; Electrocardiography - drug effects; Heart - drug effects; Heart - physiopathology; In Vitro Techniques; Ion Transport - drug effects; Male; Oocytes; Patch-Clamp Techniques; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Protein Isoforms - metabolism; Rabbits; Reperfusion Injury - complications; Reperfusion Injury - physiopathology; Sodium - metabolism; Sodium - pharmacology; Sodium-Calcium Exchanger - antagonists & inhibitors; Sodium-Calcium Exchanger - genetics; Sodium-Calcium Exchanger - metabolism; Thiourea - analogs & derivatives; Thiourea - pharmacology; Ventricular Function, Left - drug effects; Xenopus laevis
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.2001.281.3.h1334

1  Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba R2H 2A6; and 2  Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 The Na + /Ca 2+ exchanger plays a prominent role in regulating intracellular Ca 2+ levels in cardiac myocytes and can serve as both a Ca 2+ influx and efflux pathway. A novel inhibitor, KB-R7943, has been reported to selectively inhibit the reverse mode (i.e. , Ca 2+ entry) of Na + /Ca 2+ exchange transport, although many aspects of its inhibitory properties remain controversial. We evaluated the inhibitory effects of KB-R7943 on Na + /Ca 2+ exchange currents using the giant excised patch-clamp technique. Membrane patches were obtained from Xenopus laevis oocytes expressing the cloned cardiac Na + /Ca 2+ exchanger NCX1.1, and outward, inward, and combined inward-outward currents were studied. KB-R7943 preferentially inhibited outward (i.e., reverse) Na + /Ca 2+ 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 µM 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 Ca 2+ entry via reverse Na + /Ca 2+ exchange in this process. sodium/calcium; NCX1.1; giant excised patch clamp; electrophysiology