In cardiac myocytes, milrinone increases contractility by what mechanism?

In cardiac myocytes, milrinone increases contractility by what mechanism?

• A. Blocking calcium release from SR
• B. Decreasing calcium sensitivity of myofilaments
• C. Inhibiting Na+/K+ ATPase
• D. Increasing calcium influx through L-type Ca2+ channels

Answer: (D)

Milrinone works by inhibiting PDE3, which raises intracellular cAMP levels and activates protein kinase A. This cascade enhances calcium handling in the heart, boosting the amount of calcium available for contraction. A primary way this happens is by increasing calcium influx through L-type calcium channels during the action potential, because PKA phosphorylation makes these channels more likely to open and pass Ca2+ into the cell. That extra calcium enters during each beat, raising the calcium transient and strengthening the force of contraction. Milrinone also promotes calcium cycling within the cell by enhancing SERCA activity via phospholamban phosphorylation, which increases SR calcium uptake and the amount of calcium available for release on the next beat. But the hallmark mechanism that directly accounts for the inotropic rise described in the question is the increased calcium entry through L-type channels. The other options don’t fit: blocking calcium release from the SR would reduce contraction; decreasing calcium sensitivity of the myofilaments would not explain the inotropic boost seen with milrinone; inhibiting Na+/K+ ATPase is the action of digoxin, not milrinone.

Milrinone works by inhibiting PDE3, which raises intracellular cAMP levels and activates protein kinase A. This cascade enhances calcium handling in the heart, boosting the amount of calcium available for contraction. A primary way this happens is by increasing calcium influx through L-type calcium channels during the action potential, because PKA phosphorylation makes these channels more likely to open and pass Ca2+ into the cell. That extra calcium enters during each beat, raising the calcium transient and strengthening the force of contraction.

Milrinone also promotes calcium cycling within the cell by enhancing SERCA activity via phospholamban phosphorylation, which increases SR calcium uptake and the amount of calcium available for release on the next beat. But the hallmark mechanism that directly accounts for the inotropic rise described in the question is the increased calcium entry through L-type channels.

The other options don’t fit: blocking calcium release from the SR would reduce contraction; decreasing calcium sensitivity of the myofilaments would not explain the inotropic boost seen with milrinone; inhibiting Na+/K+ ATPase is the action of digoxin, not milrinone.