Phase 1 repolarization rate defines Ca²⁺ dynamics and contractility on intact mouse hearts

Area of Science:

• Cardiology
• Electrophysiology
• Molecular Cardiology

Background:

• Cardiac excitation-contraction coupling relies on calcium (Ca²⁺) influx via L-type Ca²⁺ channels.
• In most mammals, this influx occurs during action potential plateau (phase 2), but in murine models, it occurs during early repolarization (phase 1).
• The role of transient outward potassium current (I_to) in modulating this early Ca²⁺ influx in murine hearts is not fully understood.

Purpose of the Study:

• To investigate how altering 4-aminopyridine (4-AP)-sensitive Kv channels during phase 1 affects cardiac Ca²⁺ currents, Ca²⁺ transients, and systolic pressure.
• To test the hypothesis that decreasing I_to enhances Ca²⁺ influx and promotes larger Ca²⁺ transients.

Main Methods:

• Utilized pulsed local-field fluorescence microscopy and loose-patch photolysis in intact perfused beating hearts.
• Simultaneously recorded Ca²⁺ transients and action potentials (APs).
• Applied 4-aminopyridine (4-AP) to inhibit Kv channels and NS5806 to activate I_to; nifedipine was used to block L-type Ca²⁺ channels.

Main Results:

• Reducing the phase 1 repolarization rate by inhibiting Kv channels increased Ca²⁺ transient amplitude due to enhanced L-type Ca²⁺ channel influx.
• 4-AP prolonged AP repolarization time and increased Ca²⁺ transient amplitude, with greater effects in the epicardium.
• Activating I_to with NS5806 reduced Ca²⁺ current and Ca²⁺ transient amplitudes.
• The effect of 4-AP on phase 1 was diminished with partial L-type Ca²⁺ channel blockade by nifedipine.

Conclusions:

• Modulation of Kv channels during phase 1 significantly impacts cardiac Ca²⁺ influx and transients in murine hearts.
• The rate of phase 1 repolarization is determined by the interplay between outward K⁺ currents and inward Ca²⁺ currents.
• Findings highlight a critical role for early repolarization dynamics in regulating cardiac contractility.