Inward rectifier potassium currents as a target for atrial fibrillation therapy.

Subunits of inwardly rectifying potassium channels (Kir) are expressed in many different tissues of the human body. Inward rectifier currents expressed in the heart are constituted by pore-forming alpha-subunits of Kir2, Kir3, and Kir6 subfamilies. Characteristic properties of inward rectifiers comprise small outward conductances that nevertheless are important to terminal repolarization of cardiac action potentials. There is considerable difference in the regional expression of cardiac Kir channels, and subunits are additionally regulated by specific disease conditions. Resulting changes facilitate occurrence and persistence of atrial fibrillation (AF). For instance, upregulation of Kir2.1 protein and resultant current I K1 is a hallmark of AF-related ionic remodeling. Increased I K1 helps to stabilize atrial rotors, and current inhibition has accordingly been suggested as an antiarrhythmic approach for AF therapy. But there are caveats to I K1 inhibition per se, and there is no specific inhibitor of Kir2 channels. Modulation of I K1 rectification properties seems theoretically interesting for manipulation of Kir2 currents as an antiarrhythmic approach. Kir3-based muscarinic currents (I KACh) are functionally upregulated during AF through increased constitutive activity (passing current in the absence of an agonist). Upregulated I KACh supports sustenance of the arrhythmia. There is considerable intraatrial diversity in the expression of underlying Kir3.1/Kir3.4 subunits, but atrial-specific localization makes inhibition of this current a potentially interesting antiarrhythmic target devoid of ventricular side effects. Experimental studies of specific inhibitors indicate efficacy in various disease models. The role of I KATP remodeling under AF conditions has not been extensively studied, but present evidence indicates current downregulation and modulation of IKATP seems less promising than that of other inward rectifiers.