Received for publication March 4, 2008.
Revised June 3, 2008.
Accepted for publication June 4, 2008.

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

Abstract

Objective: Istaroxime (PST2744) is a novel inotropic agent which enhances SERCA2 activity. We investigated istaroxime effect on Ca²⁺ 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 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. Results: HF characterization: AoB caused hypertrophy and failure in 100% and 25% of animals respectively. While CICR-gain during constant pacing was preserved, SR Ca²⁺ content and SR Ca²⁺ uptake were strongly depressed. Resting Ca²⁺ and the slope of the 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. Istraoxime failed to increase SERCA activity in skeletal muscle microsomes devoid of phospholamban. Conclusions: 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.

Key words: Na/K pump blockers, SERCA, SR function, aortic banding, calcium handling, heart failure