Dynamic Ca2+-induced inward rectification of K+ current during the ventricular action potential

Area of Science:

• Cardiovascular Physiology
• Electrophysiology
• Molecular Cardiology

Background:

• Inward rectification, crucial for cell excitability, can be modulated by intracellular cations like calcium (Ca2+).
• The role of Ca2+-mediated rectification of inward rectifier K+ current (IK1) in the mammalian heart remains debated, often based on indirect evidence.

Purpose of the Study:

• To investigate the influence of Ca2+ on IK1 rectification during mammalian ventricular action potentials.
• To determine the contribution of Ca2+ influx and release to IK1 modulation in cardiac myocytes.

Main Methods:

• Whole-cell patch-clamp recordings from guinea pig ventricular myocytes.
• Voltage-clamp protocols mimicking the action potential waveform.
• Pharmacological blockade of L-type Ca2+ channels (dihydropyridines) and ryanodine receptors; intracellular Ca2+ buffering (BAPTA-AM).

Main Results:

• Ca2+ blockade (Ba2+ or K+-free solution) reduced IK1 during depolarization, confirming inward rectification.
• Blockade of L-type Ca2+ current and ryanodine-sensitive Ca2+ release significantly increased systolic IK1.
• Intracellular Ca2+ buffering enhanced IK1 and diminished the effects of Ca2+ channel blockade.

Conclusions:

• Physiological Ca2+ transients, from both influx and release, can significantly reduce IK1 in mammalian ventricular myocytes.
• While a fraction of total IK1 rectification, Ca2+-induced effects are substantial enough to influence cardiac excitability and repolarization.
• Ca2+-mediated IK1 modulation may contribute to early afterdepolarizations under conditions of increased Ca2+ influx.