Cardiac glycoside tolerance in cultured chicken heart muscle cells — A dose-dependent phenomenon

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Abstract
In cultured heart muscle cells from 10–13 day-old chicken embryos, the effects of acute (4 h) and chronic (3 days) exposure of the cells to varying concentrations of ouabain have been studied. In these cells, the cardiac glycoside ouabain binds to a specific cardiac glycoside receptor (KD=4 × 10−7 M; 750,000 receptors/cell). Binding to this receptor results in inhibition of active Na+/K+-transport [EC50 for active (86Rb+ + K+)-influx=4 × 10−6 M], and in an increase in beating velocity (“positive inotropic effect”;; EC50=4 × 10−7 M); toxic signs (arrhythmias) appear at concentrations ≥ 6 × 10−7 M. During exposure of the cells to 3 × 10−6 M ouabain for 3 days, tolerance develops with respect to both the positive inotropic and the toxic effect. The mechanism underlying this tolerance is identified as an increase in the number of active sodium pump molecules per cell, while the binding properties of the cardiac glycoside receptor remain unchanged. The development of cardiac glycoside tolerance is only observed in the presence of severe impairment of Na+/K+-homeostasis, due to cardiac glycoside-induced inhibition of active Na+/K+-transport. This, however, only occurs in the presence of toxic (receptor occupation ≥ 60%), but not in the presence of positive inotropic, non-toxic (receptor occupation 20–60%), ouabain concentrations. We conclude that the development of cardiac glycoside tolerance during long-term treatment in patients with heart failure should not occur with submaximal dose regimens, when toxic signs (arrhythmias) are absent.