Modulation of sarcoplasmic reticulum function by PST2744 [Istaroxime; (E,Z)-3-((2-aminoethoxy)imino) androstane-6,17-dione hydrochloride] in a pressure-overload heart failure model

PST2744 [Istaroxime; (E, Z)-3-((2-aminoethoxy)imino) androstane-6,17- dione hydrochloride)] is a novel inotropic agent that enhances sarco(endo) plasmic reticulum Ca2+ ATPase (SERCA) 2 activity. We investigated the istaroxime effect on Ca2+ handling abnormalities in myocardial hypertrophy/failure (HF). Guinea pig myocytes were studied 12 weeks after aortic banding (AoB) and compared with those of sham-operated animals (sham). The gain of calcium- induced Ca2+ release (CICR), sarcoplasmic reticulum (SR) Ca2+ content, Na+/Ca2+ exchanger (NCX) function, and the rate of SR reloading after caffeine-induced depletion (SR Ca2+ uptake, measured during NCX blockade) were evaluated by measurement of cytosolic Ca2+ and membrane currents. HF characterization: AoB caused hypertrophy and failure in 100 and 25% of animals, respectively. Although CICR gain during constant pacing was preserved, SR Ca2+ content and SR Ca2+ uptake were strongly depressed.