Abstract 15502: Role of Enhanced Late Na+ Current in the Generation of Ventricular Arrhythmias in Dahl Salt-Sensitive Rats
Dahl salt-sensitive (DSS) rat is a model of systemic hypertension leading to cardiac hypertrophy with increased incidence of ventricular arrhythmia. Enhanced cardiac late Na+ current (late INa) is arrhythmogenic. We tested the hypothesis that late INa is enhanced and contributes to ventricular arrhythmias in systemic hypertension induced cardiac hypertrophy. This study assessed the effect of GS-458967 (GS967), a potent and selective inhibitor of late INa (IC50 = 0.13 μM) in DSS rats fed with normal-salt (NS, 0.3% NaCl) or high-salt (HS, 8% NaCl) diets for 8-weeks to develop systemic hypertension and ventricular hypertrophy. Rats were treated with vehicle (NS and HS) or GS967 (1 mg/kg/day) after 3 weeks of HS diet feeding. Using whole-cell patch-clamp technique, late INa and action potentials (APs) were measured in ventricular myocytes isolated from rats fed with NS, HS or HS with GS967. Compared to NS (blue bar, Fig. A), the density of late INa was significantly increased in myocytes from HS fed rats (black bar, Fig. A, n=9). Similarly, AP duration to 50 and 90% repolarization (APD50 and APD90) was significantly prolonged in myocytes from HS fed rats (black bars, Fig. B, n=8-13). Acute application of GS967 (0.3 μM) to myocytes from HS fed rats inhibited late INa and shortened both APD50 and APD90 (red bars, Fig. A and B). Burst-pacing (3 Hz) followed by a 20 sec pause in the presence of isoproterenol (0.3 μM) induced triggered activity (TA) in 6/6 myocytes from high-salt fed rats. GS967 at 0.3 and 1 μM suppressed TA by 66 (4/6 myocytes) and 100% (4/4 myocytes), respectively. In myocytes from GS967 treated (chronic) HS rats, late INa and APD50 and APD90 were significantly reduced. Our data show that late INa is enhanced and contributes to APD prolongation and TA in HS fed rats. Selective inhibition of this current could stabilize cardiac repolarization and suppress ventricular arrhythmias associated with hypertension induced cardiac hypertrophy.
- © 2013 by American Heart Association, Inc.