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Am J Physiol Heart Circ Physiol 283: H2045-H2053, 2002; doi:10.1152/ajpheart.00203.2002
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Vol. 283, Issue 5, H2045-H2053, November 2002

Positive inotropic effects of ouabain in isolated cat ventricular myocytes in sodium-free conditions

Manabu Nishio1, Stuart W. Ruch1, and J. Andrew Wasserstrom1,2

1 Division of Cardiology, Department of Medicine, and 2 Department of Molecular Pharmacology and Biological Chemistry and the Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Illinois 60611

The inotropic and toxic effects of cardiac steroids are thought to result from Na+-K+-ATPase inhibition, with elevated intracellular Na+(Na<UP><SUB>i</SUB><SUP>+</SUP></UP>)causing increased intracellular Ca2+(Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP>) via Na-Ca exchange. We studied the effects of ouabain on cat ventricular myocytes in Na+-free conditions where the exchanger is inhibited. Cell shortening and Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP> transients (with fluo 4-AM fluorescence) were measured under voltage clamp during exposure to Na+-free solutions [LiCl or N-methyl-D-glucamine (NMDG) replacement]. Ouabain enhanced contractility by 121 ± 55% at 1 µmol/l (n = 11) and 476 ± 159% at 3 µmol/l (n = 8) (means ± SE). Ca<UP><SUB>i</SUB><SUP>2+</SUP></UP> transient amplitude was also increased. The inotropic effects of ouabain were retained even after pretreatment with saxitoxin (5 µmol/l) or changing the holding potential to -40 mV (to inactivate Na+ current). Similar results were obtained with both Li+ and NMDG replacement and in the absence of external K+, indicating that ouabain produced positive inotropy in the absence of functional Na-Ca exchange and Na+-K+-ATPase activity. In contrast, ouabain had no inotropic response in rat ventricular myocytes (10-100 µmol/l). Finally, ouabain reversibly increased Ca2+ overload toxicity by accelerating the rate of spontaneous aftercontractions (n = 13). These results suggest that the cellular effects of ouabain on the heart may include actions independent of Na+-K+-ATPase inhibition, Na-Ca exchange, and changes in Na<UP><SUB>i</SUB><SUP>+</SUP></UP>.

N-methyl-D-glucamine; cardiac glycosides; sarcoplasmic reticulum; digitalis toxicity


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