Abstract
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.
Footnotes
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This study was supported by the Istituto di Ricerche Prassis Sigma-Tau and by FAR Universita [highfalling] Milano-Bicocca to A.Z.
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Parts of this work were presented in abstract form as follows: Rocchetti M, Alemanni M, Micheletti R, Ferrari P, and Zaza A (2007) Istaroxime modulation of sarcoplasmic reticulum function in cardiac hypertrophy/failure. In Winter Meeting on Translational Basic Science of the Heart Failure Association; 2007 Jan 24–27; Garmisch-Parten Kirchen, Germany.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.138701.
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ABBREVIATIONS: SERCA, sarco(endo)plasmic reticulum Ca2+ ATPase; PST2744, (E,Z)-3-((2-aminoethoxy)imino) androstane-6,17-dione hydrochloride); SR, sarcoplasmic reticulum; PLB, phospholamban; AoB, aortic banding; HW/BW, heart weight/body weight ratio; LW/BW, lung weight/body weight ratio; Cm, membrane electrical capacity; ICaL, L-type Ca2+ current; INCX, Na+/Ca2+ exchanger current; CICR, Ca2+-induced Ca2+ release; Caf, free cytosolic Ca2+ concentration; NCX, Na+/Ca2+ exchanger; CaSRT, total sarcoplasmic reticulum Ca2+ content; Carest, resting Ca2+ at -80 mV; τdecay, time constant of Ca2+ transient relaxation; dCa/dtmax, maximum velocity of Ca2+ rise; ANOVA, analysis of variance; CV, coefficient(s) of variation; RyR, ryanodine receptor; Im, membrane current; a.u., arbitrary unit(s); Lcyt, liters of cytosol.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received March 3, 2008.
- Accepted June 4, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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