Abstract 2335: Cardiac Inward Rectifier Potassium Channels Are a Target for Antifibrillatory Pharmacophores
Ventricular tachycardia/fibrillation (VT/VF) is a major cause of sudden cardiac death. The cardiac inward rectifier channel Kir2.1 responsible for IK1 is important for controlling the frequency and stability of VT/VF. Chloroquine, an antimalarial quinoline, blocks IK1. Here, we tested the hypothesis that chloroquine’s mode of interaction with the vestibule of Kir2.1 cytoplasmic domain and the resulting geometry of drug-vestibule complex make it a more effective IK1 blocker and antifibrillatory agent than quinidine. We used optical mapping of Langendorff-perfused mouse hearts with cardiac specific IK1 upregulation and patch clamping to compare the effects of chloroquine with those of quinidine on VF dynamics, and on IK1. In 9/9 hearts, 10microM chloroquine slowed down and terminated VT/VF, due to rotor destabilization and meandering, with subsequent resumption of normal sinus rhythm. In Kir2.1-expressing HEK cells, 10microM chloroquine blocked 86±5% of barium-sensitive current. Conversely, 10mM quinidine which blocked 20±6% of IK1, failed to terminate VT/VF in 5/6 hearts, implying that IK1 blockade is essential for arrhythmia termination. Finally, we used comparative molecular modeling and ligand docking of the 3-D structures of quinidine and chloroquine in the intracellular domain of Kir2.1. Simulations suggested that chloroquine effectively blocks potassium flow by binding nonspecifically within the band of negative charge at the center of the ion permeation vestibule of Kir2.1 cytoplasmic domain. In contrast, the 42-fold less potent quinidine binds with specificity the vestibule side, partially blocking ion movement. These results open a path toward discovery of novel antiarrhythmic quinoline-derived pharmacophores that target inward rectifier channels.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).