Question

Digoxin to Inhibit \(\mathrm{Na}^{+} \mathrm{K}^{+}\)ATPase The \(\mathrm{Na}^{+} \mathrm{Ca}^{2+}\) exchanger expressed in cardiac myocytes is a bidirectional antiporter protein that removes calcium from the cytoplasm by exchanging it with sodium. Cardiac myocytes also express the \(\mathrm{Na}^{+} \mathrm{K}^{+}\)ATPase. Suppose that a \(\mathrm{Na}^{+} \mathrm{K}^{+}\)ATPase inhibitor (digoxin) is added to cardiac myocytes. Using your knowledge of the relative concentrations of ions (intracellular versus extracellular) and the important role of the \(\mathrm{Na}^{+} \mathrm{K}^{+}\)ATPase in maintaining the electrochemical gradient, what change would you expect in the intracellular \(\left[\mathrm{Ca}^{2+}\right] ?\) Why?

Short answer

Intracellular Ca2+ concentration increases due to digoxin inhibiting Na+ K+ ATPase.

Step-by-step solution

Understanding Na+ K+ ATPase Function

The Na+ K+ ATPase is an enzyme that pumps three sodium ions (Na+) out of the cell and two potassium ions (K+) into the cell, using one ATP molecule for energy. This pump helps maintain the low concentration of Na+ and high concentration of K+ inside cardiac myocytes, essential for maintaining the cell's electrochemical gradient.

Role of Na+ Ca2+ Exchanger

The Na+ Ca2+ exchanger uses the sodium gradient established by the Na+ K+ ATPase to export one calcium ion (Ca2+) from the cell in exchange for importing three Na+ ions. This helps in reducing the intracellular calcium concentration, which is crucial for muscle relaxation after contraction.

Effect of Digoxin

Digoxin inhibits the Na+ K+ ATPase, leading to reduced Na+ export from the cell and thus increased intracellular Na+ concentration. This disrupts the sodium gradient that the Na+ Ca2+ exchanger relies on.

Impact on Intracellular Ca2+ Concentration

With the Na+ Ca2+ exchanger less effective due to a decreased sodium gradient (resulting from Na+ K+ ATPase inhibition), less calcium is removed from the cell. As a consequence, the intracellular concentration of Ca2+ increases.

Key concepts

Na+ K+ ATPase Inhibition

The Na+ K+ ATPase enzyme is crucial in maintaining the electrolyte balance across a cell membrane. Think of it as a tiny molecular pump that uses energy from ATP to move ions in and out of the cell. Specifically, it pumps three sodium ions (Na+) out and two potassium ions (K+) into the cell. This activity is essential for maintaining the cell's electrochemical gradient, which is like a battery for the cell.
When substances like digoxin inhibit Na+ K+ ATPase, this careful balance gets disrupted. Sodium builds up inside the cell because it is not being pumped out as effectively. Without the proper functioning of Na+ K+ ATPase, the whole ionic balancing act of the cell is thrown off, affecting many cellular processes and potentially causing the cell to behave differently.

Na+ Ca2+ Exchanger

The Na+ Ca2+ exchanger is another important component in cardiac cells, working in harmony with the Na+ K+ ATPase. Its role is to regulate calcium levels inside the cell by exporting calcium ions (Ca2+) in exchange for importing sodium ions (Na+).
This exchanger essentially uses the high concentration of sodium outside the cell—created by the Na+ K+ ATPase pump—to efficiently remove calcium. Typically, for each calcium ion moving out, three sodium ions move in. It's like a seesaw balancing act that ensures cardiac cells don't store too much calcium, which could affect muscle contraction and relaxation.

• Maintains low levels of intracellular Ca2+
• Relies on the sodium gradient created by the Na+ K+ ATPase

When this balance is disrupted, as with Na+ K+ ATPase inhibition, calcium starts accumulating inside the cell.

Digoxin Mechanism

Digoxin is a medication known to inhibit Na+ K+ ATPase. By blocking this pump, digoxin increases the concentration of sodium within the cardiac myocytes. This increase in sodium concentration inside the cell causes the sodium gradient across the cell membrane to decrease.
This declined gradient has a significant impact on how the Na+ Ca2+ exchanger operates. Essentially, with more intracellular sodium, the exchanger's ability to export calcium decreases. Instead of calcium leaving the cell, it tends to stick around more.
In a therapeutic context, this mechanism is actually useful because a higher intracellular calcium level strengthens heart muscle contraction, which can be beneficial in certain heart conditions.

Intracellular Calcium Concentration

Intracellular calcium concentration is critical for heart muscle function. Calcium is the superstar of muscle contraction; it binds to specific proteins within the muscle cells to trigger the contraction process.
However, too much calcium can lead to dangerous over-contractions or incomplete muscle relaxation. Normally, cells manage calcium levels very tightly using systems like the Na+ Ca2+ exchanger.
With Na+ K+ ATPase inhibition (as seen with digoxin usage), calcium clearance is reduced, leading to increased intracellular calcium.

• Enhanced calcium levels can cause more vigorous heart muscle contractions
• Can help improve heart function in conditions like heart failure
• But must be monitored to avoid unwanted side effects

Effective calcium regulation is essential for supporting healthy cardiac rhythms and preventing muscle fatigue or damage.