Abstract 567: Aldosterone Modulates Gap Junction Remodeling in Cultured Rat Ventricular Myocytes
Background and Objectives: A variety of stresses impact the heart and the renin-angiotensin-aldosterone system (RAAS) affects cellular structure and electrophysiology. Modulation of intercellular coupling through gap junction could lead to an alteration in conduction velocity and conduction block. The aim of this study was to investigate the effects of aldosterone (Ald) on the expression of connexin (Cx)43 gap junction in neonatal rat cultured ventricular myocytes and the consequence changes of conduction properties.
Methods: Culture was exposed to Ald for 24h. The expression of Cx43 was characterized by western blotting and real-time RT-PCR. Propagation of excitation was visualized by extracellular potential mapping by using a multiple electrode array system.
Results: Exposure to 10-4 M Ald resulted in a significant downregulation of Cx43 (by ~0.4-fold in protein). Treatment with 10-8 M Ald induced a significant increase of Cx43 (by ~1.4-fold in protein and by ~1.3-fold in mRNA). Conduction velocity was increased significantly by the treatment of 10-8 M Ald (~20% increase) with a random propagation of contraction. Ald is known to bind to two types of binding sites: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). To clarify the effects of dose dependency of Ald on Cx43 expression, Ald was applied to cardiomyocytes pretreated with GR antagonist (mifepristone) or MR antagonist (eplerenone). Mifepristone inhibited the decrease of Cx43 of cardiomyocytes exposed to 10-4 M Ald. The increase of Cx43 of cardiomyocytes exposed to 10-8 M Ald was prevented by eplerenone. On the other hand, losartan did not affect the alterations in Cx43 expression caused by 10-4 and 10-8 Ald exposure.
Conclusions: These results suggest that Ald affects gap junction remodeling in a dose dependent manner by modulating Cx43 synthesis through a different receptor and causes a concomitant change of conduction velocity. An effective prevention of RAAS activation during development of gap junction remodeling might be a new therapeutic strategy for the treatment of arrhythmias.