Selective Inhibition of Pulmonary Vein Excitability by Constitutively Active GIRK Channels Blockade in Rats

Area of Science:

• Electrophysiology
• Cardiovascular Research
• Molecular Cardiology

Background:

• Pulmonary veins (PV) are a primary source of ectopic beats that trigger atrial fibrillation.
• G protein-coupled inwardly rectifying potassium (GIRK) channels play a role in cardiac electrical activity.

Purpose of the Study:

• To investigate the role and distribution of GIRK channels in the rat pulmonary veins (PV) and left atrium (LA).
• To determine if GIRK channels in the PV could serve as a molecular target for electrical disconnection from the LA.

Main Methods:

• Simultaneous intracellular microelectrode recordings from the LA and PV of rats.
• Patch-clamp recordings from isolated PV and LA myocytes.
• Application of GIRK channel blocker tertiapin-Q.
• Western blot analysis for GIRK subunit expression.
• Experiments using ROMK1 and KCa1.1 channel blockers to rule out off-target effects.

Main Results:

• Tertiapin-Q induced action potential duration (APD) prolongation in the LA and abolished the overshoot in PV action potentials, indicating constitutively active GIRK channels in both tissues.
• Patch-clamp studies revealed tertiapin-Q inhibited a basal inwardly rectified current in PV cells but had minimal effect on LA cells.
• Western blot analysis showed significantly higher GIRK4 subunit expression in PV cardiomyocytes compared to LA cardiomyocytes.

Conclusions:

• GIRK channels are constitutively active in rat PV and LA, with greater expression of the GIRK4 subunit in PV cardiomyocytes.
• Blockade of GIRK channels selectively abolishes action potentials in the PV, but not the LA.
• GIRK channels represent a potential molecular target for achieving electrical disconnection of the PV from the LA, offering a novel approach for atrial fibrillation treatment.