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CARDIOVASCULAR

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

Dipartimento di Biotecnologie e Bioscienze, Università Milano-Bicocca, Milano, Italy (M.R., M.A., G.M., C.A., R.C., A.Z.); and Prassis Sigma-Tau Research Institute, Settimo Milanese, Italy (P.B., R.M., P.F.)

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 (I_NCX)/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 I_NCX/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.

Address correspondence to: Dr. Antonio Zaza, Dipartimento di Biotecnologie e Bioscienze, Università degli Studi Milano-Bicocca, P.zza della Scienza 2, 20126 Milano, Italy. E-mail: antonio.zaza{at}unimib.it

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