PT  - JOURNAL ARTICLE
AU  - Arici, Martina
AU  - Ferrandi, Mara
AU  - Barassi, Paolo
AU  - Hsu, Shih-Che
AU  - Torre, Eleonora
AU  - Luraghi, Andrea
AU  - Ronchi, Carlotta
AU  - Chang, Gwo-Jyh
AU  - Peri, Francesco
AU  - Ferrari, Patrizia
AU  - Bianchi, Giuseppe
AU  - Rocchetti, Marcella
AU  - Zaza, Antonio
TI  - Istaroxime Metabolite PST3093 Selectively Stimulates SERCA2a and Reverses Disease-Induced Changes in Cardiac Function
AID  - 10.1124/jpet.122.001335
DP  - 2023 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 231--244
VI  - 384
IP  - 1
4099  - http://jpet.aspetjournals.org/content/384/1/231.short
4100  - http://jpet.aspetjournals.org/content/384/1/231.full
SO  - J Pharmacol Exp Ther2023 Jan 01; 384
AB  - Heart failure (HF) therapeutic toolkit would strongly benefit from the availability of ino-lusitropic agents with a favorable pharmacodynamics and safety profile. Istaroxime is a promising agent, which combines Na+/K+ pump inhibition with sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) stimulation; however, it has a very short half-life and extensive metabolism to a molecule named PST3093. The present work aims to investigate whether PST3093 still retains the pharmacodynamic and pharmacokinetic properties of its parent compound. We studied PST3093 for its effects on SERCA2a and Na+/K+ ATPase activities, Ca2+ dynamics in isolated myocytes, and hemodynamic effects in an in vivo rat model of diabetic [streptozotocin (STZ)-induced] cardiomyopathy. Istaroxime infusion in HF patients led to accumulation of PST3093 in the plasma; clearance was substantially slower for PST3093 than for istaroxime. In cardiac rat preparations, PST3093 did not inhibit the Na+/K+ ATPase activity but retained SERCA2a stimulatory activity. In in vivo echocardiographic assessment, PST3093 improved overall cardiac performance and reversed most STZ-induced abnormalities. PST3093 intravenous toxicity was considerably lower than that of istaroxime, and it failed to significantly interact with 50 off-targets. Overall, PST3093 is a “selective” SERCA2a activator, the prototype of a novel pharmacodynamic category with a potential in the ino-lusitropic approach to HF with prevailing diastolic dysfunction. Its pharmacodynamics are peculiar, and its pharmacokinetics are suitable to prolong the cardiac beneficial effect of istaroxime infusion.SIGNIFICANCE STATEMENT Heart failure (HF) treatment would benefit from the availability of ino-lusitropic agents with favourable profiles. PST3093 is the main metabolite of istaroxime, a promising agent combining Na+/K+ pump inhibition and sarcoplasmic reticulum Ca2+ ATPase2a (SERCA2a) stimulation. PST3093 shows a longer half-life in human circulation compared to istaroxime, selectively activates SERCA2a, and improves cardiac performance in a model of diabetic cardiomyopathy. Overall, PST3093 as a selective SERCA2a activator can be considered the prototype of a novel pharmacodynamic category for HF treatment.