Istaroxime, a positive inotropic agent devoid of proarrhythmic properties in sensitive chronic atrioventricular block dogs

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Alexandre BossuMarc A Vos

Abstract

Current inotropic agents in heart failure therapy associate with low benefit and significant adverse effects, including ventricular arrhythmias. Istaroxime, a novel Na+/K+-transporting ATPase inhibitor, also stimulates SERCA2a activity, which would confer improved inotropic and lusitropic properties with less proarrhythmic effects. We investigated hemodynamic, electrophysiological and potential proarrhythmic and antiarrhythmic effects of istaroxime in control and chronic atrioventricular block (CAVB) dogs sensitive to drug-induced Torsades de Pointes arrhythmias (TdP). In isolated normal canine ventricular cardiomyocytes, istaroxime (0.3-10 μM) evoked no afterdepolarizations and significantly shortened action potential duration (APD) at 3 and 10 μM. Istaroxime at 3 μg/kg/min significantly increased left ventricular (LV) contractility (dP/dt+) and relaxation (dP/dt-) respectively by 81 and 94% in anesthetized control dogs (n = 6) and by 61 and 49% in anesthetized CAVB dogs (n = 7) sensitive to dofetilide-induced TdP. While istaroxime induced no ventricular arrhythmias in control conditions, only single ectopic beats occurred in 2/7 CAVB dogs, which were preceded by increase of short-term variability of repolarization (STV) and T...Continue Reading

Citations

Oct 3, 2019·Arrhythmia & Electrophysiology Review·Agnieszka SmoczynskaMarc A Vos
Oct 6, 2020·Frontiers in Physiology·Alexandra NjegicElizabeth J Cartwright
Jul 19, 2020·International Journal of Molecular Sciences·Bruno Bragança, Paulo Correia-de-Sá
Mar 9, 2021·British Journal of Pharmacology·Vera LoenMarcel A G van der Heyden
Jul 6, 2021·Journal of the American Heart Association·María Florencia RacioppiMartín Vila Petroff

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