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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 6, 2008; DOI: 10.1124/jpet.108.138701

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Marcella Rocchetti
Matteo Alemanni
Gaspare Mostacciuolo
Paolo Barassi
Claudia Altomare
Riccardo Chisci
Rosella Micheletti
Patrizia Ferrari
Antonio Zaza
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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

Marcella Rocchetti 1, Matteo Alemanni 1, Gaspare Mostacciuolo 1, Paolo Barassi 2, Claudia Altomare 1, Riccardo Chisci 1, Rosella Micheletti 2, Patrizia Ferrari 2, Antonio Zaza 1*

1 Universita Milano-Bicocca 2 Prassis Sigma-Tau

* Address correspondence to: E-mail: antonio.zaza{at}unimib.it

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 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. 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


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