Topics on the Na+/Ca2+ exchanger: involvement of Na+/Ca2+ exchange system in cardiac triggered activity.

Sodium-calcium exchange (NCX) is one of the major regulators of intracellular Ca(2+) concentration in cardiac myocytes. The bi-directional and electrogenic property of NCX raises a question about whether NCX is involved in arrhythmias. We reviewed the role of NCX in cardiac triggered activity in limited experimental conditions: the digitalis-induced arrhythmia, the arrhythmia caused from sustained opening of sodium channel, and the arrhythmia caused from the inhibition of inwardly rectifying potassium current. Effects of NCX inhibitors on ventricular arrhythmias recorded on ECG or the delayed afterdepolarizations and triggered activity recorded by the current clamp method were evaluated. As an NCX inhibitor, we preferred to use SEA0400 instead of KB-R 7943. For a precise analysis, a computational reconstruction of action potential with the Luo and Rudy model was applied. The cardiac NCX system seems to play a role only in the digitalis-induced arrhythmia and may not be involved in other arrhythmias. This review highlights the relationship between triggered activity and an NCX system and also suggests the physiologic and pathologic aspect of the NCX system in cardiac arrhythmias.

Effects of sodium-calcium exchange inhibitors, KB-R7943 and SEA0400, on aconitine-induced arrhythmias in guinea pigs in vivo, in vitro, and in computer simulation studies.

The sodium-calcium exchange (NCX) plays a pivotal role in regulating contractility and electrical activity in the heart. However, the effects of NCX blockers on ventricular arrhythmias are still controversial. We examined the effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine-induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501-1526) for ventricular myocytes, we simulated abnormal membrane activity produced by NCX inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10 mg/kg of SEA did not suppress these arrhythmias. There was a difference in isolated ventricular myocytes also. KBR (10 microM) suppressed abnormal electrical activity induced by aconitine, but SEA (100 microM) did not show such effects. KBR (10 microM) significantly changed the shape of the action potential configurations (action potential duration at 50% repolarization), but SEA (1-100 microM) did not change these configurations. In the computer simulation study, the aconitine-induced abnormal electrical activity was mimicked by a negative shift of the kinetics of Na+ channels, and this was followed by additional suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors), which enhanced abnormal membrane activity. Our results indicate that the inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from a mechanism other than the inhibition of NCX, and thus the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias.

Pharmacology of KB-R7943: a Na+-Ca2+ exchange inhibitor.

The Na+-Ca2+ exchange (NCX) system plays a pivotal role in regulating intracellular Ca2+ concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB-R9743 (KBR) that appears to exhibit selectivity for Ca2+-influx-mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN-6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases.