TY - JOUR T1 - Modulation of Sarcoplasmic Reticulum Function by PST2744 [Istaroxime; (<em>E</em>,<em>Z</em>)-3-((2-Aminoethoxy)imino) Androstane-6,17-dione Hydrochloride)] in a Pressure-Overload Heart Failure Model JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 957 LP - 965 DO - 10.1124/jpet.108.138701 VL - 326 IS - 3 AU - Marcella Rocchetti AU - Matteo Alemanni AU - Gaspare Mostacciuolo AU - Paolo Barassi AU - Claudia Altomare AU - Riccardo Chisci AU - Rosella Micheletti AU - Patrizia Ferrari AU - Antonio Zaza Y1 - 2008/09/01 UR - http://jpet.aspetjournals.org/content/326/3/957.abstract N2 - 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. Resting Ca2+ and the slope of the Na+/Ca2+ exchanger current (INCX)/Ca2+ relationship were unchanged by AoB. Istaroxime effects: CICR gain, SR Ca2+ content, and SR Ca2+ uptake rate were increased by istaroxime in sham myocytes and, to a significantly larger extent, in AoB myocytes; this led to almost complete recovery of SR Ca2+ uptake in AoB myocytes. Istaroxime increased resting Ca2+ and the slope of the INCX/Ca2+ relationship similarly in sham and AoB myocytes. Istaroxime failed to increase SERCA activity in skeletal muscle microsomes devoid of phospholamban. Thus, clear-cut abnormalities in Ca2+ handling occurred in this model of hypertrophy, with mild decompensation. Istaroxime enhanced SR function more in HF myocytes than in normal ones; almost complete drug-induced recovery suggests a purely functional nature of SR dysfunction in this HF model. The American Society for Pharmacology and Experimental Therapeutics ER -