Cardiac Myocyte Action Potential Phases

The cardiac myocyte action potential is the electrical heartbeat of life, dictating every contraction that pumps blood through your body. Understanding its five distinct phases is not just academic; it's fundamental to grasping how the heart functions normally, what goes wrong in arrhythmias, and how many cardiac drugs work. For MCAT takers and future physicians, this knowledge is a high-yield target that bridges basic physiology with clinical medicine.

The Foundation: Resting Membrane Potential and Ion Gradients

Before diving into the action potential, you must understand the starting point. Cardiac ventricular myocytes maintain a stable resting membrane potential of approximately $-90\text{ mV}$ (millivolts) inside the cell relative to the outside. This negative voltage is Phase 4 of the action potential cycle. It is established primarily by the concentration gradients of key ions—high extracellular sodium (${\text{Na}}^{+}$) and calcium (${\text{Ca}}^{2+}$), and high intracellular potassium (${\text{K}}^{+}$)—and the selective permeability of the cell membrane at rest. At rest, the membrane is highly permeable to potassium via inward rectifier potassium channels ($I_{K1}$). Potassium efflux driven by its concentration gradient creates a negative interior, balanced by the sodium-potassium pump (${\text{Na}}^{+}/{\text{K}}^{+}$-ATPase). This stable phase is crucial; any deviation can lead to abnormal automaticity, a concept frequently tested on the MCAT in the context of arrhythmogenesis.

Phase 0: Rapid Depolarization – The Electrical Trigger

Depolarization is the rapid shift of the membrane potential from negative to positive. Phase 0 is initiated when a sufficient stimulus, typically from a neighboring cell, depolarizes the membrane to a critical threshold (about $-70\text{ mV}$). This voltage change rapidly opens voltage-gated fast sodium channels. The resulting massive sodium influx ($I_{Na}$) causes the membrane potential to skyrocket from $-90\text{ mV}$ to approximately $+20\text{ to }+30\text{ mV}$ in milliseconds. This upstroke is responsible for the rapid conduction of the electrical impulse throughout the ventricles, ensuring synchronized contraction. On the MCAT, a common trap is to confuse this with neuronal action potentials; while both use sodium influx, the cardiac phase 0 is followed by a unique plateau, making the overall duration much longer.

Phases 1 and 2: The Unique Cardiac Plateau

Immediately after the peak of depolarization, Phase 1, or initial repolarization, begins. The fast sodium channels inactivate, and a transient outward potassium current ($I_{to}$) is activated, leading to a brief potassium efflux. This causes a small, rapid dip in potential, setting the stage for the hallmark of cardiac myocytes: the plateau phase (Phase 2).

Phase 2 is a delicate balance where depolarization is maintained for 100-200 milliseconds. This is achieved by a precise counterbalance of inward and outward currents. The primary inward current is mediated by L-type calcium channels (slow calcium channels), which open in response to the depolarization and allow a sustained calcium influx ($I_{Ca-L}$). This calcium entry is critical for initiating cardiac muscle contraction via calcium-induced calcium release from the sarcoplasmic reticulum. Balancing this inward current is a slow potassium efflux through delayed rectifier potassium channels ($I_K$). The near-equilibrium of these opposing flows creates the characteristic flat plateau on an action potential tracing. This extended depolarization ensures a prolonged refractory period, preventing tetanic contraction and allowing the heart to fill with blood—a vital concept for MCAT questions on cardiac muscle versus skeletal muscle physiology.

Phase 3: Repolarization – Returning to Rest

Repolarization is the process of restoring the negative resting potential. During Phase 3, the L-type calcium channels gradually inactivate, reducing the inward calcium current. Simultaneously, the delayed rectifier potassium currents ($I_K$) intensify, leading to a dominant potassium efflux. This net outward flow of positive charge drives the membrane potential back down toward the resting level. The repolarization phase is steep and brings the potential from the plateau level back to $-90\text{ mV}$. The restoration of the resting potential also involves the reactivation of the inward rectifier potassium channels ($I_{K1}$), which stabilize the membrane at Phase 4. Understanding the sequence of channel inactivation and activation here is key to predicting the effects of drugs that block specific channels, a classic MCAT and clinical pharmacology scenario.

Ion Channel Orchestration and Clinical Integration

The five-phase sequence is a tightly orchestrated symphony of ion channel openings and closings. Here’s a integrated view:

• Phase 0: Fast sodium channels open (${\text{Na}}^{+}$ in).
• Phase 1: Fast sodium channels inactivate; transient outward potassium channels open (${\text{K}}^{+}$ out).
• Phase 2: L-type calcium channels open (${\text{Ca}}^{2+}$ in) balanced by delayed rectifier potassium channels (${\text{K}}^{+}$ out).
• Phase 3: L-type calcium channels inactivate; delayed rectifier potassium channels remain open (${\text{K}}^{+}$ out dominates).
• Phase 4: Inward rectifier potassium channels maintain rest (${\text{K}}^{+}$ out at rest).

From an MCAT and clinical perspective, this ion channel basis explains everything from electrocardiogram (ECG) waveforms to drug actions. For instance, Class I antiarrhythmic drugs block fast sodium channels, slowing Phase 0 depolarization and conduction velocity. Class III drugs block potassium channels, prolonging Phase 3 repolarization and the action potential duration, which can be therapeutic or pro-arrhythmic. When analyzing a scenario, always trace the effect back to a specific phase and ion current.

Common Pitfalls

1. Confusing the roles of sodium and calcium: A frequent MCAT trap is attributing the entire depolarization to calcium or the plateau to sodium. Remember: sodium influx is solely responsible for the rapid upstroke (Phase 0). Calcium influx is responsible for sustaining the plateau (Phase 2) and triggering contraction.
2. Misunderstanding the resting potential: It’s easy to think the resting potential is maintained by the ${\text{Na}}^{+}/{\text{K}}^{+}$-ATPase pump alone. While the pump establishes the gradients, the immediate resting potential ($-90\text{ mV}$) is primarily due to the high resting permeability to potassium via $I_{K1}$ channels. The pump is electrogenic but contributes only a few millivolts directly.
3. Overlooking the purpose of the plateau: Students often memorize the plateau without understanding its physiological consequence. The key takeaway is that the long action potential duration due to the plateau creates a long absolute refractory period. This prevents summation and tetanus, allowing the heart to relax and fill between beats—a critical distinction from skeletal muscle.
4. Equating all potassium currents: The various potassium currents ($I_{to}$, $I_K$, $I_{K1}$) activate at different times and have distinct roles. For example, $I_{to}$ shapes Phase 1, while $I_K$ drives Phase 3. On exams, pay close attention to the timing described in the question stem.

Summary

• The ventricular cardiac action potential has five phases (0-4) defined by specific ion movements across the myocyte membrane.
• Phase 0 is rapid depolarization due to voltage-gated fast sodium channel opening and massive sodium influx.
• Phase 1 is initial repolarization caused by a transient outward potassium efflux.
• Phase 2 is the prolonged plateau phase where calcium influx through L-type channels is balanced by potassium efflux, enabling sustained contraction and preventing tetanus.
• Phase 3 is rapid repolarization driven by dominant potassium efflux as calcium channels inactivate.
• Phase 4 is the stable resting potential maintained at $-90\text{ mV}$ by inward rectifier potassium channels.