Antiarrhythmic and Inotropic Effects of Selective Na+/Ca2+ Exchanger Inhibition: What Can We Learn from the Pharmacological Studies?

Abstract

Life-long stable heart function requires a critical balance of intracellular Ca2+. Several ion channels and pumps cooperate in a complex machinery that controls the influx, release, and efflux of Ca2+. Probably one of the most interesting and most complex players of this crosstalk is the Na+/Ca2+ exchanger, which represents the main Ca2+ efflux mechanism; however, under some circumstances, it can also bring Ca2+ into the cell. Therefore, the inhibition of the Na+/Ca2+ exchanger has emerged as one of the most promising possible pharmacological targets to increase Ca2+ levels, to decrease arrhythmogenic depolarizations, and to reduce excessive Ca2+ influx. In line with this, as a response to increasing demand, several more or less selective Na+/Ca2+ exchanger inhibitor compounds have been developed. In the past 20 years, several results have been published regarding the effect of Na+/Ca2+ exchanger inhibition under various circumstances, e.g., species, inhibitor compounds, and experimental conditions; however, the results are often controversial. Does selective Na+/Ca2+ exchanger inhibition have any future in clinical pharmacological practice? In this review, the experimental results of Na+/Ca2+ exchanger inhibition are summarized focusing on the data obtained by novel highly selective inhibitors.

The inotropic and arrhythmogenic effects of acutely increased late INa are associated with elevated ROS but not oxidation of PKARIα

“…Instead, in our murine model, diastolic Ca 2+ overload and increased Ca 2+ transient amplitudes are presumably a consequence of increased NCX activity in its reverse mode leading to severe cytosolic Ca 2+ overload, since ATX-II does not enhance transsarcolemmal Ca 2+ influx via the LTCC (which would be an alternative mechanism of cytosolic Ca 2+ overload, see the following). While this effect may be different in larger animals and humans ( 41 ), our observation would be in line with previous reports that have demonstrated that inhibition of NCX significantly attenuates intracellular Ca 2+ overload and also reduces arrhythmias upon increased I NaL ( 30 , 42 ). In contrast to our previous study ( 23 ), in which oxidized PKARIα maintained I Ca upon oxidative stress, we failed to detect any functional effect of ATX-II treatment on the amplitude or the inactivation properties of I Ca in both WT and KI cells here (while I Ca was slightly but significantly enhanced in KI vs. WT upon ATX-II treatment in the face of a generally lower I Ca amplitude in WT cells).…”

The Antiarrhythmic Action of the Na⁺/Ca²⁺ Exchanger Inhibitor SEA0400 on Drug-Induced Long QT Syndrome Depends on the Severity of Proarrhythmic Conditions in Anesthetized Atrioventricular Block Rabbits

“…This effect can be explained by the inhibition of the forward mode of NCX, which contributes to the generation of a depolarization current, leading to repolarization prolongation and EAD generation. 7,9) Meanwhile, as shown in Figs. 3 and 4, SEA0400 hardly affected MAP prolongation and EAD generation after treatment with high-dose nifekalant but could suppress TdP.…”

“…Na + /Ca 2+ exchanger (NCX) has been recognized to be involved in the proarrhythmic mechanism of TdP, and its forward mode generates inward current by exchanging one intracellular Ca 2+ for three extracellular Na + , contributing to the induction of EAD. 7) Moreover, NCX is expected to become a therapeutic target for the prevention of TdP since ventricular contractility has been shown to be unaffected by NCX inhibitors. 6,8) In previous experiments, the typical I Kr blocker dofetilide-induced TdP has been demonstrated to be effectively suppressed by the specific NCX inhibitor SEA0400 in a canine in vivo model of chronic atrioventricular block (AVB).…”

Perimenopause Decreases SERCA2a Activity in the Hearts of a Mouse Model of Ovarian Failure

“…The increased reliance on Na + –Ca 2+ exchangers to remove intracellular calcium is an imbalanced mechanism that results in the net gain of positive charges in the cell. This imbalance is known to increase the risk of cardiac arrhythmias [ 33 ], a common cause of acute post-myocardial infarction mortality [ 15 , 16 , 17 ]. While the changes in calcium handling could drive an increased risk for these pathologies, it should be noted that menopause itself is generally not sufficient to cause cardiac disease.…”