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Cardiovascular Research 2007 75(1):109-117; doi:10.1016/j.cardiores.2007.03.017
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Copyright © 2007, European Society of Cardiology

The Na+/K+-ATPase {alpha}2-isoform regulates cardiac contractility in rat cardiomyocytes

Fredrik Swifta,b,*, Nils Tovsruda,b, Ulla H. Engera,b, Ivar Sjaastada,b,c and Ole M. Sejersteda,b

aInstitute for Experimental Medical Research, Ullevaal University Hospital, University of Oslo, Oslo, Norway
bCenter for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway
cDepartment of Cardiology, Ullevaal University Hospital, Oslo, Norway

* Corresponding author. Institute for Experimental Medical Research, Ullevål University Hospital, 4th floor Department of Surgery, Kirkeveien 166, N-0407 Oslo, Norway. Tel.: +47 23016800; fax: +47 23016799. fredrik.swift{at}medisin.uio.no

Objective The presence of both {alpha}1- and {alpha}2-isoforms of the Na+/K+-ATPase (NKA) in cardiomyocytes indicates different functions. We hypothesized that preferential localization of the {alpha}2-isoform to the t-tubules, locally controlling the Na+/Ca2+-exchanger (NCX), underlies a specific role in Ca2+ handling.

Methods We studied NKA isoform distribution in isolated cardiomyocytes from Wistar rats using immunocytochemistry. NKA pump and NCX currents (Ipump and INCX) were measured in control and detubulated cardiomyocytes. Intracellular Na+ concentration [Na+]i was assessed with the fluorescent dye SBFI.

Results The {alpha}2-isoform abundance was higher in the t-tubules than in the surface sarcolemma. We established that 0.3 µM ouabain specifically blocked the {alpha}2-isoform in isolated rat cardiomyocytes. This low concentration blocked 10.7±0.6% of Ipump in control, but only 6.0±0.5% in detubulated cardiomyocytes. Moreover, measured and calculated {alpha}1-specific and {alpha}2-specific Ipump in control (547±29 pA and 66 pA, respectively) and in detubulated cells (495±30 pA and 31 pA, respectively) showed that 53% of the {alpha}2-isoform, but only 9.5% of the {alpha}1-isoform, were localized to the t-tubules. Despite the small abundance of the {alpha}2-isoform (~11% of total NKA), selective inhibition of this isoform induced a 40% increase in contractility in field stimulated cardiomyocytes, but no increase in global [Na+]i. However, inhibition of the {alpha}2-isoform increased INCX indicating local subsarcolemmal accumulation of Na+ near NCX.

Conclusions The {alpha}2-isoform of the NKA is functionally coupled to the NCX and can regulate Ca2+ handling without changing global [Na+]i.

KEYWORDS Contractile function; e–c coupling; Ions; Ion pumps; Na/K-pump


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F. Swift, J. A. K. Birkeland, N. Tovsrud, U. H. Enger, J. M. Aronsen, W. E. Louch, I. Sjaastad, and O. M. Sejersted
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