Abstract:
:Cardiac glycosides like ouabain are used in the therapy of heart failure and atrial fibrillation. They exert a positive inotropic effect on cardiomyocytes by inhibiting the plasma membrane sodium pump (Na,K-ATPase), decreasing the Ca-extrusion by the sarcolemmal cardiac sodium/calcium exchanger (NCX) and increasing the intracellular Ca-concentration and Ca-release during subsequent contraction cycles.The longer term effects of ouabain treatment on the expression of proteins important for Ca- and Na-homeostasis are not well known and were investigated in this study. Isolated adult rat cardiomyocytes were cultured in the presence or absence of ouabain (30 microM). In these cells, the expression of the Na,K-ATPase, Na,Ca-exchanger (NCX), the sarcoplasmic reticulum Ca-ATPase (SERCA 2a) and phospholamban (PLB) were studied by Western blot. In addition, the contractile function of these cells was studied after electrical stimulation. After 2 days of ouabain treatment immunoreactivity of the NCX was increased significantly relative to control which was set 1 (1.78 +/- 0.16 vs. 1 +/- 0.13; n = 8; P = 0.003) and at day 4 (1.96 +/- 0.35 vs. 1 +/- 0.20; n = 6; P = 0.02). All other proteins (SERCA 2a, PLB and Na,K-ATPase a1 and b1) remained unchanged (n >/= 4). Ouabain treatment increased the fractional shortening of isolated cardiomyocytes at day 0 (1 Hz: 9.64 +/- 0.73 %, n = 24, vs. 7.18 +/- 0.60 %; n = 21; P = 0.01), whereas at day 2 the contractility was unchanged (1 Hz: 7.23 +/- 1.08 %, n = 9 vs. 7.70 +/- 0.63 %; n = 10, P = 0.71). The inhibition of SERCA 2a (10 microM cyclopiazonic acid (CPA)) decreased contractility in both the ouabain treated group and in controls, at day 0 and at day 2. These results show that chronic ouabain treatment increases the protein expression of the NCX. The positive inotropic effect of ouabain can no longer be observed after a chronic treatment for 2 days. Thus, both protein expression and contractile function of the cells are specifically altered by longer term cardiac glycoside exposure. Whether such regulation can be found in human cardiomyocytes and the resulting consequences in the clinical setting remain to be determined.
journal_name
Basic Res Cardioljournal_title
Basic research in cardiologyauthors
Müller-Ehmsen J,Nickel J,Zobel C,Hirsch I,Bölck B,Brixius K,Schwinger RHdoi
10.1007/s00395-003-0396-9keywords:
subject
Has Abstractpub_date
2003-03-01 00:00:00pages
90-6issue
2eissn
0300-8428issn
1435-1803journal_volume
98pub_type
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