Modulation of sarcoplasmic reticulum function by istaroxime (PST2744) in a pressure-overload heart failure model

Objective: Istaroxime (PST2744) is a novel inotropic agent which enhances SERCA2 activity. We investigated istaroxime effect on Ca(2+) handling abnormalities in myocardial hypertrophy/failure (HF). Methods: guinea-pig myocytes were studied 12 weeks after aortic banding (AoB) and compared to those of sham-operated animals (sham). The gain of calcium-induced Ca(2+) release (CICR), sarcoplasmic reticulum (SR) Ca(2+) content, Na(+)/Ca(2+) exchanger (NCX) function and the rate of SR reloading after caffeine-induced depletion (SR Ca(2+) uptake, measured during NCX blockade) were evaluated by measurement of cytosolic Ca(2+) and membrane currents. Results: HF characterization: AoB caused hypertrophy and failure in 100% and 25% of animals respectively. While CICR-gain during constant pacing was preserved, SR Ca(2+) content and SR Ca(2+) uptake were strongly depressed. Resting Ca(2+) and the slope of the INCX/Ca(2+) relationship were unchanged by AoB. Istaroxime effects: CICR gain, SR Ca(2+) content and SR Ca(2+) 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 Ca(2+) uptake in AoB myocytes. Istaroxime increased resting Ca(2+) and the slope of the INCX/Ca(2+) relationship similarly in sham and AoB myocytes. Istraoxime failed to increase SERCA activity in skeletal muscle microsomes devoid of phospholamban. Conclusions: Clear-cut abnormalities in Ca(2+) 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.