Digitalis receptors in cardiac cells and their relation with positive inotropic and cardiotoxic effects

Area of Science:

• Cardiovascular Physiology
• Cellular Pharmacology
• Biochemistry

Background:

• The cardiac sodium-potassium adenosine triphosphatase ((Na+,K+)ATPase) is a key regulator of intracellular ion concentrations.
• Ouabain is a cardiac glycoside known to interact with (Na+,K+)ATPase, but its precise mechanisms of action at different concentrations are not fully elucidated.

Purpose of the Study:

• To investigate the biochemical and pharmacological properties of (Na+,K+)ATPase in chick embryonic hearts.
• To determine the relationship between ouabain binding affinity, ion transport, and cardiotonic/cardiotoxic effects.

Main Methods:

• Studied intact chick embryonic hearts and cultured cardiac cells.
• Assessed ouabain binding sites, 86Rb+ uptake, intracellular Na+ concentration, and 45Ca2+ uptake.
• Evaluated inotropic effects of ouabain on papillary muscle and ventricular cells.

Main Results:

• Identified two ouabain binding sites: low affinity (2-6 microM) and high affinity (26-48 nM).
• Low affinity site saturation correlated with (Na+,K+)ATPase inhibition, increased intracellular Na+, and stimulated Ca2+ uptake via Na+/Ca2+ exchange.
• Cardiotonic effects of ouabain paralleled low affinity site saturation.

Conclusions:

• Inhibition of cardiac (Na+,K+)ATPase at low affinity binding sites mediates both the beneficial cardiotonic and detrimental cardiotoxic effects of ouabain.
• The Na+/Ca2+ exchange system plays a crucial role in ouabain's indirect effects on intracellular calcium.