How does inhibiting the sodium-potassium (Na+/K+) pump increase intracellular calcium levels?

From the Guidelines

Inhibiting the sodium-potassium (Na+/K+) pump increases intracellular calcium levels by reducing the sodium gradient across the cell membrane, which affects the sodium-calcium exchanger and leads to increased calcium influx. This process is crucial in understanding how certain medications, like digoxin, exert their effects on the heart. According to 1, digoxin inhibits the sodium-potassium ATPase pump in myocardial cells, producing a transient increase in intracellular calcium that results in an influx of calcium to increase myocardial contractility.

The mechanism behind this increase in intracellular calcium involves several key steps:

• The inhibition of the Na+/K+ pump leads to sodium accumulation inside the cell.
• This increased intracellular sodium concentration reduces the sodium gradient across the cell membrane.
• The reduced sodium gradient affects the sodium-calcium exchanger (NCX), which normally uses the sodium gradient to remove calcium from the cell.
• With a diminished sodium gradient, NCX works less efficiently or reverses direction, resulting in reduced calcium efflux or even calcium influx.
• Additionally, membrane depolarization from sodium accumulation can activate voltage-gated calcium channels, allowing more calcium to enter the cell, as noted in the context of how digoxin increases cardiac contractility 1.

This understanding is critical for the clinical use of drugs like digoxin, which must be carefully dosed to avoid calcium overload and toxicity, especially in patients with specific conditions such as renal impairment or electrolyte abnormalities. The typical dose of digoxin, such as 0.125-0.25 mg daily, reflects the need to balance therapeutic efficacy with the risk of adverse effects related to excessive intracellular calcium levels.

From the FDA Drug Label

Inhibition of the enzyme leads to an increase in the intracellular concentration of sodium and thus (by stimulation of sodium-calcium exchange) an increase in the intracellular concentration of calcium

• Inhibiting the sodium-potassium (Na+/K+) pump increases intracellular calcium levels by:
  • Increasing the intracellular concentration of sodium
  • Stimulating sodium-calcium exchange, which leads to an increase in the intracellular concentration of calcium 2

From the Research

Inhibition of the Sodium-Potassium Pump and Its Effect on Intracellular Calcium Levels

• The inhibition of the sodium-potassium (Na+/K+) pump can lead to an increase in intracellular calcium levels, as evidenced by studies such as 3 and 4.
• This increase in intracellular calcium is primarily due to the rise in intracellular sodium concentrations, which in turn increases Na+/Ca2+ exchange, thereby raising intracellular Ca2+ levels 3.
• The Na+/Ca2+ exchanger plays a crucial role in this process, as it transports three Na+ ions into the cytoplasm in exchange for one Ca2+ moved out, thus regulating intracellular Ca2+ levels 5.
• Other sarcolemmal cation channels and exchangers, such as the Na+/H+ exchanger and L-type Ca2+ channels, may also be involved in modifying the increase in intracellular calcium on inhibiting Na+-K+-ATPase 6.

Mechanisms of Sodium-Potassium Pump Inhibition

• The sodium-potassium pump can be inhibited by various means, including the use of cardiac glycosides such as digitalis, which bind to the Na+-K+ ATPase and reduce its activity 7.
• Inhibition of the sodium-potassium pump can also occur due to decreased Na+ efflux or increased Na+ influx into the myocyte, leading to an increase in intracellular Na+ concentrations 4.
• The increase in intracellular Na+ can have multiple effects on the heart, including influencing intracellular Ca2+ and pH levels, thereby modulating heart contractility 5.

Consequences of Increased Intracellular Calcium

• The increase in intracellular calcium levels can have significant consequences, including interfering with normal contractile activity in cardiac and skeletal muscle, and resistance to vasodilation in vascular smooth muscle 3.
• In cardiac myocytes, the increase in intracellular calcium can lead to arrhythmogenesis and diastolic dysfunction, particularly in conditions such as heart failure and hypertrophic cardiomyopathy 4.
• The increase in intracellular calcium can also lead to nervous tone, as evidenced by the ability of sodium-potassium pump inhibition to increase nervous tone by decreasing the membrane potential and allowing more efficient depolarization of nerve endings 3.