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Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current
1Department of Medicine, University of Chicago, IL 60637.
Abstract:
Early afterdepolarizations (EADs) are a type of triggered activity found in heart muscle. We used voltage-clamped sheep cardiac Purkinje fibers to examine the mechanism underlying EADs induced near action potential plateau voltages with the Ca2+ current agonist Bay K 8644 and the effect of several interventions known to suppress or enhance these EADs. Bay K 8644 produced an inward shift of the steady-state current-voltage relation near plateau voltages. Tetrodotoxin, lidocaine, verapamil, nitrendipine, and raising [K]o abolish EADs and shift the steady-state current-voltage relations outwardly. Using a two-pulse voltage-clamp protocol, an inward current transient was present at voltages where EADs were induced. The voltage-dependence of availability of the inward current transient and of EAD induction were similar. The time-dependence of recovery from inactivation of the inward current transient and of EAD amplitude were nearly identical. Without recovery of the inward current transient, EADs could not be elicited. The inward current transient was enhanced with Bay K 8644 and blocked by nitrendipine, but was not abolished by tetrodotoxin or replacement of [Na]o with an impermeant cation. These results support a hypothesis that the induction of EADs near action potential plateau voltages requires 1) a conditioning phase controlled by the sum of membrane currents present near the action potential plateau and characterized by lengthening and flattening of the plateau within a voltage range where, 2) recovery from inactivation and reactivation of L-type Ca2+ channels to carry the depolarizing charge can occur. Our results suggest an essential role for the L-type Ca2+ "window" current and provide a framework for understanding the role of several membrane currents in the induction and block of EADs.
Insights
Early afterdepolarizations (EADs) are triggered heart activity. This study shows EADs require L-type calcium channel recovery and a specific membrane current, crucial for understanding EADs and developing treatments.
Area of Science:
- Cardiac Electrophysiology
- Ion Channel Function
- Arrhythmogenesis
Background:
- Early afterdepolarizations (EADs) are a form of triggered cardiac activity.
- EADs are associated with potentially life-threatening arrhythmias.
- Understanding the ionic mechanisms of EADs is critical for therapeutic development.
Purpose of the Study:
- To investigate the ionic mechanisms underlying EADs induced near action potential plateau voltages.
- To examine the role of the L-type calcium current in EAD generation.
- To determine the effects of various interventions on EADs.
Main Methods:
- Utilized voltage-clamped sheep cardiac Purkinje fibers.
- Employed the Ca2+ current agonist Bay K 8644 to induce EADs.
- Applied a two-pulse voltage-clamp protocol to study inward current transients.
Main Results:
- Bay K 8644 induced an inward shift in steady-state current-voltage relations.
- EAD induction correlated with the voltage-dependence and time-dependence of an inward current transient.
- Tetrodotoxin, lidocaine, verapamil, nitrendipine, and increased extracellular potassium abolished EADs.
Conclusions:
- EAD induction requires a conditioning phase and recovery/reactivation of L-type Ca2+ channels.
- The L-type Ca2+ "window" current plays an essential role in EAD generation.
- These findings provide a framework for understanding EAD induction and blockade.
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