Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology

摘要

PurposeMechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch.MethodsAtrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n=28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3M).ResultsOn comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3M. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3M diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (13826ms vs 95 +/- 9ms; p0.01), ventricular refractoriness (155 +/- 18ms vs 124 +/- 16 ms; p0.01) and increments in spectral concentration (23 +/- 5 vs 17 +/- 2; p0.01), the fifth percentile of ventricular activation intervals (46 +/- 8ms vs 31 +/- 3ms; p0.05), and wavelength of ventricular fibrillation (2.5 +/- 0.5cm vs 1.7 +/- 0.3cm; p0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control=38, 0.03M=33, 0.1M=33, 0.3M=14; p0.01) and the stretch-induced increments in arrhythmia complexity index (control=62, 0.03M=41, 0.1M=32, 0.3M=16; p0.05) progressively decreased on increasing the GS967 concentration.Conclusions GS967 attenuates stretch-induced changes in cardiac electrophysiology.