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High-affinity ouabain binding site and low-dose positive inotropic effect in rat myocardium

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Abstract

The mechanism of the positive inotropic effect of digitalis glycosides remains unclear. One theory suggests a causal relationship between the binding to and consequent inhibition of (Na++K+) ATPase (the sodium pump) by digitalis and an increased myocardial contractile force1–6. By this mechanism, the increased force of contraction would occur secondary to an elevation of intracellular sodium concentration which then causes an increased intracellular concentration of calcium via a sodium–calcium exchange mechanism4–6. Another theory proposes that the binding of digitalis to (Na++K+) ATPase causes an increase in a sarcolemmal calcium pool6–9, suggesting that the inotropic effect could be due to a causal relationship between the formation of the digitalis–(Na++K+)ATPase receptor complex and increased myocardial calcium availability and utilization, exclusive of an inhibition of the sodium pump7–9. We now report that two distinct positive inotropic sites for ouabain exist in rat ventricular strips. The higher-affinity response (ED50 = 0.5 µM) correlates with an apparent high-affinity site which can be detected by 3H-ouabain binding to intact rat ventricular myocytes. These higher-affinity sites do not correlate with concentrations (IC50) of ouabain necessary to inhibit (Na++K+)ATPase activity of sarcolemma preparations prepared from rat ventricles, suggesting that in the rat ventricle the high-affinity site for the inotropic effect of ouabain may not be related to inhibition of (Na++K+)ATPase. The low-affinity site is, however, related to inhibition of this enzyme.

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Authors and Affiliations

  1. Departments of Pharmacology and Cell Biophysics, Physiology and Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA

    Robert J. Adams, Arnold Schwartz, Gunther Grupp, Ingrid Grupp, Shin-Woong Lee & Earl T. Wallick

  2. Department of Physics as Applied to Medicine, Middlesex Hospital Medical School, London, WIP 7PN, UK

    Trevor Powell, Victor W. Twist & Premjith Gathiram

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  1. Robert J. Adams
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  2. Arnold Schwartz
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  3. Gunther Grupp
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  4. Ingrid Grupp
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  5. Shin-Woong Lee
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  6. Earl T. Wallick
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  7. Trevor Powell
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  8. Victor W. Twist
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  9. Premjith Gathiram
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Adams, R., Schwartz, A., Grupp, G. et al. High-affinity ouabain binding site and low-dose positive inotropic effect in rat myocardium. Nature 296, 167–169 (1982). https://doi.org/10.1038/296167a0

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