| In Vitro | In vitro activity: GS967 (also known as GS-458967) is a novel, potent, and selective sodium channel inhibitor exhibiting potent antiarrhythmic effects in various in vitro and in vivo models. It inhibit cardiac late sodium current (late INa ) with IC50 values of 0.13 and 0.21 μM for ventricular myocytes and isolated hearts, respectively. The antiarrhythmic mechanism of GS967 has been attributed to preferential suppression of late sodium current. GS967 (10, 100, 300 nM) completely attenuates the effect of ATX-II (10 nM) to increase action potential duration (APD) and APD variability in ventricular myocytes, with an apparent IC50 value of ~10 nM and decreased the beat-to-beat variability of APD. GS967 selectively suppressed late I(Na) and prevented and/or reduced the incidence of experimentally induced arrhythmias in rabbit myocytes and hearts.
Kinase Assay:
Cell Assay: GS967 at10, 100, 300 nM completely attenuates the effect of ATX-II (10 nM) to increase action potential duration (APD) and APD variability in ventricular myocytes, with an apparent IC50 value of ~10 nM and decreased the beat-to-beat variability of APD |
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| In Vivo | GS967 prevents and reverses proarrhythmic effects of the late INa enhancer ATX-II and the IKr inhibitor E-4031. GS967 significantly attenuates the proarrhythmic effects of methoxamine 1 clofilium and suppressed ischemia-induced arrhythmias. GS967 causes a reduction of INaP in a frequency-dependent manner, consistent with use-dependent block (UDB). GS967 evokes more potent UDB of INaP (IC50=0.07 μM) than ranolazine (16 μM) and lidocaine (17 μM). GS967 is found to exert these same effects on a prototypical long QT syndromemutation (delKPQ). GS967 prevents ischemia-induced increases in alternans in the left atrium and left ventricle. GS967 reduces ischemia-induced increases in depolarization heterogeneity and repolarizationheterogeneity. GS967 does not alter heart rate, arterial blood pressure, PR and QT intervals, or QRS duration, but it mildly decreased contractility during ischemia, which was consistent with late INa inhibition |
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