SAR340835, a Novel Selective Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, Improves Cardiac Function and Restores Sympathovagal Balance in Heart Failure

Pelat, Michel; Barbe, Fabrice; Daveu, Cyril; Ly-Nguyen, Laetitia; Lartigue, Thomas; Marque, Suzanne; Tavares, Georges; Ballet, Véronique; Guillon, Jean‐Michel; Steinmeyer, Klaus; Wirth, Klaus; Gögelein, Heinz; Arndt, Petra; Rackelmann, Nils; Weston, John B.; Bellevergue, Patrice; McCort, Gary; Trellu, Marc; Lucats, Laurence; Beauverger, Philippe; Pruniaux-Harnist, Marie-Pierre; Janiak, Philip; Chézalviel-Guilbert, Frédérique

doi:10.1124/jpet.120.000238

Cited by 7 publications

(13 citation statements)

References 44 publications

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“…The pharmacodynamic profile of SAR296968 has been described elsewhere [ 20 ]. To analyze the effect of SAR296968 on triggered atrial activity, confocal laser scanning microscopy was performed in Fluo-4 loaded myocytes.…”

Section: Resultsmentioning

confidence: 99%

“…To date, pharmacological NCX inhibition has been broadly tested in animal models, including rodents and large species [ 14 , 20 , 21 ]. However, to our knowledge, translation of specific NCX inhibitors to human cardiac tissue has not yet been performed.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, the safety of SAR296968 has been studied. In a recent study, SAR296968 did not cause relevant inhibition of I Na or I Ca in vitro nor prolongation of the QT interval in vivo while providing high pharmacological selectivity with an IC 50 of 74 nM for human NCX1 [ 20 ]. In addition, Pelat et al measured the NCX currents in guinea pig cardiomyocytes and Chinese Hamster Ovary cells expressing human NCX isoforms.…”

Section: Discussionmentioning

confidence: 99%

“…NCX activity in forward mode can increase transient inward current resulting in delayed afterdepolarizations [ 19 ]. Recently, pharmacological NCX inhibitors improved cardiac function and displayed antiarrhythmic properties in guinea pigs and dog hearts [ 20 , 21 ]. Additionally, cardiac function in a murine HFpEF model was improved by NCX inhibition [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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

Hegner¹,

Drzymalski²,

Biedermann³

et al. 2022

Biomedicines

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hegner¹,

Drzymalski²,

Biedermann³

et al. 2022

Biomedicines

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“…Therefore, further investigations are needed to elucidate the mechanism of action of safranal, taking into account that (1) most of the available Na + /Ca 2+ exchanger inhibitors hitherto are lacking selectivity since they interfere with other ionic currents such as L-type Ca 2+ current and K + (I Kir ) currents. Only recently, some more specific Na + /Ca 2+ exchanger inhibitors were reported, and they are in an experimental stage [43,44].…”

Section: Discussionmentioning

confidence: 99%

Safranal Induces Vasorelaxation by Inhibiting Ca2+ Influx and Na+/Ca2+ Exchanger in Isolated Rat Aortic Rings

Al-Saigh

Abdalla

2022

Molecules

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Introduction: Safranal, which endows saffron its unique aroma, causes vasodilatation and has a hypotensive effect in animal studies, but the mechanisms of these effects are unknown. In this study, we investigated the mechanisms of safranal vasodilation. Methods: Isolated rat endothelium-intact or -denuded aortic rings were precontracted with phenylephrine and then relaxed with safranal. To further assess the involvement of nitric oxide, prostaglandins, guanylate cyclase, and phospholipase A2 in safranal-induced vasodilation, aortic rings were preincubated with L-NAME, indomethacin, methylene blue, or quinacrine, respectively, then precontracted with phenylephrine, and safranal concentration–response curves were established. To explore the effects of safranal on Ca2+ influx, phenylephrine and CaCl2 concentration–response curves were established in the presence of safranal. Furthermore, the effect of safranal on aortic rings in the presence of ouabain, a Na+-K+ ATPase inhibitor, was studied to explore the contribution of Na+/Ca2+ exchanger to this vasodilation. Results: Safranal caused vasodilation in endothelium-intact and endothelium-denuded aortic rings. The vasodilation was not eliminated by pretreatment with L-NAME, indomethacin, methylene blue, or quinacrine, indicating the lack of a role for NO/cGMP. Safranal significantly inhibited the maximum contractions induced by phenylephrine, or by CaCl2 in Ca2+-free depolarizing buffer. Safranal also relaxed contractions induced by ouabain, but pretreatment with safranal totally abolished the development of ouabain contractions. Discussion/Conclusion: Inhibition of Na+-K+ ATPase by ouabain leads to the accumulation of Na+ intracellularly, forcing the Na+/Ca2+ exchanger to work in reverse mode, thus causing a contraction. Inhibition of the development of this contraction by preincubation with safranal indicates that safranal inhibited the Na+/Ca2+ exchanger. We conclude that safranal vasodilation is mediated by the inhibition of calcium influx from extracellular space through L-type Ca2+ channels and by the inhibition of the Na+/Ca2+ exchanger.

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Control of Ca2+ and metabolic homeostasis by the Na+/Ca2+ exchangers (NCXs) in health and disease

Rodrigues

Piccirillo

Magi

et al. 2022

Biochemical Pharmacology

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SAR340835, a Novel Selective Na⁺/Ca²⁺ Exchanger Inhibitor, Improves Cardiac Function and Restores Sympathovagal Balance in Heart Failure

Cited by 7 publications

References 44 publications

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

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

Safranal Induces Vasorelaxation by Inhibiting Ca2+ Influx and Na+/Ca2+ Exchanger in Isolated Rat Aortic Rings

Control of Ca2+ and metabolic homeostasis by the Na+/Ca2+ exchangers (NCXs) in health and disease

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SAR340835, a Novel Selective Na+/Ca2+ Exchanger Inhibitor, Improves Cardiac Function and Restores Sympathovagal Balance in Heart Failure

Cited by 7 publications

References 44 publications

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

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

Safranal Induces Vasorelaxation by Inhibiting Ca2+ Influx and Na+/Ca2+ Exchanger in Isolated Rat Aortic Rings

Control of Ca2+ and metabolic homeostasis by the Na+/Ca2+ exchangers (NCXs) in health and disease

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SAR340835, a Novel Selective Na⁺/Ca²⁺ Exchanger Inhibitor, Improves Cardiac Function and Restores Sympathovagal Balance in Heart Failure