SAR296968, a Novel Selective Na+/Ca2+ Exchanger Inhibitor, Improves Ca2+ Handling and Contractile Function in Human Atrial Cardiomyocytes

Abstract

Background: In reverse-mode, cardiac sodium-calcium exchanger (NCX) can increase the cytoplasmic Ca2+ concentration in response to high intracellular Na+ levels, which may contribute to diastolic contractile dysfunction. Furthermore, increased spontaneous Ca2+ release from intracellular stores can activate forward mode NCX. The resulting transient inward current causes delayed afterdepolarization (DAD)-dependent arrhythmias. Moreover, recently, NCX has been associated with impaired relaxation and reduced cardiac function in heart failure with preserved ejection fraction (HFpEF). Since NCX is upregulated in human chronic atrial fibrillation (AF) as well as heart failure (HF), specific inhibition may have therapeutic potential. Objective: We tested the antiarrhythmic, lusitropic and inotropic effects of a novel selective NCX-inhibitor (SAR296968) in human atrial myocardium. Methods and Results: Right atrial appendage biopsies of 46 patients undergoing elective cardiac surgery in a predominant HFpEF cohort (n = 24/46) were investigated. In isolated human atrial cardiomyocytes, SAR296968 reduced the frequency of spontaneous SR Ca2+ release events and increased caffeine transient amplitude. In accordance, in isolated atrial trabeculae, SAR296968 enhanced the developed tension after a 30 s pause of electrical stimulation consistent with reduced diastolic sarcoplasmic reticulum (SR) Ca2+ leak. Moreover, compared to vehicle, SAR296968 decreased steady-state diastolic tension (at 1 Hz) without impairing developed systolic tension. Importantly, SAR296968 did not affect the safety parameters, such as resting membrane potential or action potential duration as measured by patch clamp. Conclusion: The novel selective NCX-inhibitor SAR296968 inhibits atrial pro-arrhythmic activity and improves diastolic and contractile function in human atrial myocardium, which may have therapeutic implications, especially for treatment of HFpEF.

Inhibition of Voltage-Gated Na+ Currents Exerted by KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea), an Inhibitor of Na+-Ca2+ Exchanging Process

“…(i) The molecular docking of KB-R7943 to hNa V 1.2 or hNa V 1.7 was predicted because of the presumed formation of both hydrophobic contacts and hydrogen bonds. Taken together, the experimental results therefore allow us to reflect that, in concert with the inhibitory effect on the reverse mode of the NCX exchanging process in varying cell types [ 6 , 7 , 40 , 46 , 61 , 66 , 67 , 68 , 69 ], KB-R7943-mediated perturbations in I Na(T) , I Na(L) , I Na(W) , I Na(R) , and I Na(P) tend to be independent of KB-R7943’s suppressive action on the activity of the NCX exchanging process. Therefore, these actions are anticipated to participate in potential modifications of the functional activities (e.g., various firing patterns) in electrically excitable cells.…”

“…The Na + -Ca 2+ (NCX) exchanger is recognized to be an important regulator of intracellular Ca 2+ concentration that is expressed in cardiac sarcolemma but also in brain, skeletal muscle, and endocrine tissues [ 1 , 2 , 3 , 4 , 5 , 6 ]. KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea) is an isothiourea derivative which is thought to selectively inhibit the reverse mode of NCX isoform 1 (NCX1) with effective IC 50 of 1.2–2.4 μM [ 7 ].…”

“…Therefore, apart from its inhibition of the NCX exchanging process, the issue of how or whether KB-R7943 or other relevant compounds could exercise any modifications on plasmalemmal ionic currents has not yet been studied. The NCX activity could be indirectly altered by changes in the magnitude of voltage-gated Na + current ( I Na ) [ 3 , 5 , 6 ]. Therefore, it is worthwhile to reappraise the ionic mechanism of KB-R7943 actions which may exist in different types of ionic currents, particularly at I Na , because significant modifications in magnitude and gating kinetics of this current have been recently investigated for their therapeutic or pharmacological effectiveness [ 11 , 12 , 13 , 14 , 15 , 16 ].…”

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

“…Human atrial APD 90 was unchanged when SAR296968, a novel, selective NCX inhibitor compound, was used. Similarly, action potential amplitude and resting potential remained unaltered after selective NCX inhibition ( Figure 7 ) [ 90 ].…”

“…In 2022, Hegner et al used a novel, selective NCX inhibitor SAR296968 on human atrial myocytes [ 90 ]. It was found that 3 µM SAR296968 increased the SR Ca 2+ content and, in 300 nM and in 3 µM, increased the developed tension in human atrial trabeculae.…”