Abstract 11926: Pharmacological Targeting of Late Na+ Current Reduces Cardiac Ventricular Action Potential Sensitivity to Small Electrical Perturbations
Selective inhibition of late Na+ current (INaL) in patients with inherited (e.g. Long QT syndrome type-3), or acquired conditions, such as ischemia and heart failure, is expected to confer therapeutic benefit by reducing the incidence of arrhythmia triggers. Recently, a novel compound that preferentially reduces INaL, GS-458967 (GS967, IC50 for block of INaL = 130 nM) was developed. Experimental measurements of the effects of GS967 on endogenous INaL in guinea pig ventricular myocytes indicate a robust concentration-dependent reduction in action potential duration (APD). Using these data to calibrate INaL amplitude in the Faber-Rudy computationally based model of the guinea pig ventricular AP, we simulated effects of GS967 on APD and observed a comparable concentration-dependent reduction in APD with INaL block (0.1μM GS967 caused 40% block of INaL in experiments leading to 12.6% APD shortening, while the model predicted 10.7% APD shortening with 40% block of INaL). An additional effect of INaL block is to reduce the time during which the membrane resides in a high resistance state. To test the hypothesis that targeted block of INaL would reduce membrane plateau resistance and make cells less susceptible to small electrical perturbations, we used the computational model to test the degree of APD prolongation induced by random injection of small current -0.1 to -0.2 pA/pF for 100 ms throughout the action potential plateau (between 30 and 200 ms) during 1 Hz pacing (Figure). The model predicted a dramatic reduction in sensitivity to small electrical perturbations as evidenced by APD90 variability in the presence of INaL block (no INaL block (A), INaL block (B)). Using a combined experimental and theoretical approach, our results suggest that INaL block is a potential therapeutic strategy to reduce membrane resistance and consequent markedly decreased sensitivity to small electrical perturbations that promote arrhythmia triggers.
- © 2013 by American Heart Association, Inc.