Abstract 18503: Geranylgeranylacetone (gga) And Gga-derivatives Inhibit Acetylcholine-activated K+ Current In Mouse Atrial Cardiomyocyte ; Possible Mechanism For Af Suppression
Atrial fibrillation (AF) is the most common sustained arrhythmia. AF is caused by inflammation, oxidative stress, and various structural heart diseases. An important key factor in AF promotion is that atrial cardiomyocytes have constitutively active acetylcholine-activated K+ (IKACh) current that is enhanced by the tachycardia. Furthermore, it is known that heat shock proteins (HSPs) are involved in the protection against different forms of cellular stress and recent investigators reported that the HSP inducing compound geranylgeranylacetone (GGA, also known as teprenone) prevents atrial remodeling and attenuates the promotion of AF. Whether GGA and GGA-derivatives prevent the acetylcholine-activated K+ current is unknown.
Methods: We examined the effect of HSP inducer GGA and 5 derivatives on IKACh current in mouse atrial cardiomyocytes. In the present study, the IKACh current was recorded using a nystatin-perforated whole cell patch-clamp technique following activation by acetylcholine (10 μM for 2 min). After the measurement of the baseline IKACh current, atrial cardiomyocytes were treated with GGA 10μM or a derivative of GGA (NYK9274, NYK9308, NYK9354, NYK9356 or NYK9376) for 10min and the IKACh current was re-measured.
Results: IKACh current in mouse atrial cardiomyocyte treated with acetylcholine (10 μM) was significantly increased, which was markedly attenuated by GGA 10μM treatment (n=5, peak; 54±11.2%, quasi-steady-state; 58±11.4%, p<0.001). In addition, the effects of the GGA derivatives on IKACh were evaluated with same experimental protocol. Our results showed that next to GGA, also NYK9308 and NYK9356 significantly inhibit both peak and quasi-steady-state IKACh. In contrast, NYK9274, NYK9354 and NYK9376 had no effect on IKACh.
Conclusion: This study provides important evidences that the HSP inducer GGA facilitates its potent antiarrhythmic effect by inhibiting IKAch, which underlies electrical remodeling in mammalian atrial cardiomyocytes. Furthermore, two GGA derivatives, NYK9308 and NYK9356, with improved pharma-chemical properties compared to GGA, reveal similar protective effects compared to GGA, and provide important background information for the use of GGA and GGA-like compounds in patients with AF.
Author Disclosures: T. Cha: None. E. Choi: None. H. Yun: None. G. Yu: None. S. Im: None. B. Brundel: None.
- © 2015 by American Heart Association, Inc.