Pelat, Michel published the artcileSAR340835, a novel selective Na+/Ca2+ exchanger inhibitor, improves cardiac function and restores sympathovagal balance in heart failure, Application of Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is sodium calcium exchanger cardiac arrhythmia heart failure.
In failing hearts, Na+/Ca2+ exchanger (NCX) overactivity contributes to Ca2+ depletion leading to contractile dysfunction. Inhibition of NCX is expected to normalize Ca2+ mishandling, to limit after depolarization-related arrhythmias and to improve cardiac function in heart failure (HF). SAR340835/SAR296968 (NCXi) potently inhibited all NCX isoforms across species with no effect on the native voltage-dependent calcium and sodium currents in vitro. Addnl., it showed in vitro and in vivo anti-arrhythmic properties in several models of early and delayed afterdepolarization-related arrhythmias. Its effect on cardiac function was studied under i.v. infusion at 250 – 750 or 1500 μg/kg/h in dogs either normal or submitted to chronic ventricular pacing at 240 bpm (HF dogs). HF dogs were infused with the reference inotrope dobutamine (10 μg/kg/min i.v.). In normal dogs NCX inhibitor increased cardiac contractility (dP/dtmax), stroke volume (SV) and tended to reduce heart rate (HR). In HF dogs NCX inhibitor significantly and dose-dependently increased SV from the first dose (+28.5%, +48.8%, +62% at 250, 750 and 1500 μg/kg/h resp.) while increasing significantly dP/dtmax only at 1500 (+33%). Furthermore, NCX inhibitor significantly restored sympathovagal balance and spontaneous baroreflex sensitivity (BRS) from the first dose and reduced HR at the highest dose. In HF dogs, dobutamine significantly increased dP/dtmax , SV (+68.8%) but did not change HR, sympathovagal balance nor BRS. Overall, SAR340835 a selective potent NCXi displayed a unique therapeutic profile, combining anti-arrhythmic properties, capacity to restore systolic function, sympathovagal balance and BRS in HF dogs. NCX inhibitors may offer new therapeutic options for acute HF treatment.
Journal of Pharmacology and Experimental Therapeutics published new progress about Antiarrhythmics. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Application of Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.