gs-458967 and Atrial-Fibrillation

Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca

Topics: Adult; Atrial Fibrillation; Calcium; Cnidarian Venoms; ERG1 Potassium Channel; Heart Atria; Humans; Membrane Potentials; Models, Cardiovascular; Myocytes, Cardiac; Piperidines; Pyridines; Ranolazine; Sodium; Triazoles

The role of the Na

Topics: Action Potentials; Animals; Atrial Fibrillation; Cells, Cultured; Diastole; Guinea Pigs; Lidocaine; Male; Membrane Potentials; Myocytes, Cardiac; Pulmonary Veins; Pyridines; Sodium; Tetrodotoxin; Triazoles

Studies demonstrated that the incidence of atrial fibrillation is significantly increased in patients with diabetes mellitus. Increase of late sodium current (I

Topics: Action Potentials; Animals; Atrial Fibrillation; Diabetes Mellitus, Experimental; Electrophysiological Phenomena; Male; Mice; Mice, Inbred C57BL; Pyridines; Sodium; Sodium Channel Blockers; Triazoles

Mechanical 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.. Atrial 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 0.3 μM).. On comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3 μM. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3 μM diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (138 ± 26 ms vs 95 ± 9 ms; p < 0.01), ventricular refractoriness (155 ± 18 ms vs 124 ± 16 ms; p < 0.01) and increments in spectral concentration (23 ± 5% vs 17 ± 2%; p < 0.01), the fifth percentile of ventricular activation intervals (46 ± 8 ms vs 31 ± 3 ms; p < 0.05), and wavelength of ventricular fibrillation (2.5 ±0.5 cm vs 1.7 ± 0.3 cm; p < 0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control = 38%, 0.03 μM = 33%, 0.1 μM = 33%, 0.3 μM = 14%; p < 0.01) and the stretch-induced increments in arrhythmia complexity index (control = 62%, 0.03μM = 41%, 0.1 μM = 32%, 0.3 μM = 16%; p < 0.05) progressively decreased on increasing the GS967 concentration.. GS967 attenuates stretch-induced changes in cardiac electrophysiology.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Disease Models, Animal; Dose-Response Relationship, Drug; Isolated Heart Preparation; Male; Mechanoreceptors; Mechanotransduction, Cellular; Myocytes, Cardiac; Pyridines; Rabbits; Refractory Period, Electrophysiological; Sodium Channel Blockers; Sodium Channels; Time Factors; Triazoles; Ventricular Fibrillation

The anti-atrial fibrillation (AF) effects of GS-458967 (GS-967), a selective, potent inhibitor of cardiac late Na(+) current (I(Na)), were evaluated in a novel model of AF induction that does not require electrical stimuli.. In 6 closed-chest anesthetized pigs, AF was induced by intrapericardial acetylcholine (1 mL of 100 mM solution) followed within 1 minute by epinephrine (20 μg/kg, i.v., bolus over 1 min). Effects of GS-967 (0.4 mg/kg, i.v., infused over 30 min) on inducibility and duration of AF were analyzed. Administration of acetylcholine followed by epinephrine elicited spontaneous AF that persisted for 12.03 ± 1.22 minutes (mean ± SEM) in all 6 pigs. Following GS-967, AF did not occur in 5 of 6 pigs when plasma concentration was 383 ± 150 nM. In the single animal in which AF could still be induced, the arrhythmia lasted 6.3 minutes. Partial return of AF inducibility occurred in 2 of 6 animals at 90 minutes, when plasma concentration of GS-967 was 228 ± 35 nM. GS-967 reduced the QT interval (P = 0.004), consistent with cardiac late I(Na) inhibition, but did not affect heart rate, mean arterial pressure, QRS duration, or PR interval. Epinephrine infusion alone, tested in a separate group (N = 6), did not provoke AF.. Selective cardiac late I(Na) inhibition with GS-967 suppresses spontaneous induction of AF in a novel model that does not require provocative electrical stimuli. Because this mode of action has only a mild on effect on contractility, it offers an advantage over contemporary anti-AF agents, which can have negative inotropic actions.

Topics: Acetylcholine; Animals; Anti-Arrhythmia Agents; Arterial Pressure; Atrial Fibrillation; Autonomic Nervous System Diseases; Electric Stimulation; Electrocardiography; Epinephrine; Heart Rate; Male; Pyridines; Sodium Channel Blockers; Sus scrofa; Swine; Triazoles

Ischemic heart disease is associated with dual risk for atrial and ventricular arrhythmias.. We examined whether selectively targeting late sodium channel current (INa) with GS-458967 (hereafter GS967) can reduce cardiac electrical instability and compared its effects to a clinically relevant dose of flecainide.. Electrode catheters were positioned on the left atrial appendage and left ventricle of anesthetized pigs to monitor repolarization alternans and electrocardiographic heterogeneity before and during left circumflex coronary artery stenosis (75% flow reduction) before and after GS967 (0.4 mg/kg, intravenously [IV]) or flecainide (1 mg/kg, IV, bolus over 2 minutes followed by 1 mg/(kg·h), IV, for 1 hour) administration.. Left circumflex coronary artery stenosis increased atrial repolarization alternans by 520% (from 9.4 ± 1.2 to 58.3 ± 11.3 μV; P = .029) and T-wave alternans by 1038% (from 30.7 ± 8.2 to 349.3 ± 103.8 μV; P = .049). GS967 prevented ischemia-induced increases in alternans in the left atrium (19.3 ± 5.6 μV vs 58.3 ± 11.3 μV; P = .023) and left ventricle (217.9 ± 95.8 μV vs 349.3 ± 103.8 μV; P < .001) (n = 7). GS967 reduced ischemia-induced increases in depolarization heterogeneity (atrium: from 45% to 28%; ventricle: from 92% to 51%) and repolarization heterogeneity (atrium: 43% to 23%; ventricle: 137% to 91%). GS967 did not alter heart rate, arterial blood pressure, PR and QT intervals, or QRS duration, but it mildly decreased contractility (left ventricular dP/dt) during ischemia, which was consistent with late INa inhibition. Flecainide (n = 7) amplified ischemia-induced increase in atrial and ventricular repolarization alternans, electrocardiographic heterogeneity, and ventricular fibrillation incidence.. Selective late INa inhibition with GS967 exerts potent protective effects against ischemia-induced depolarization and repolarization abnormalities in both atria and ventricles.

Topics: Animals; Atrial Fibrillation; Coronary Stenosis; Dose-Response Relationship, Drug; Electrocardiography; Heart Conduction System; Injections, Intravenous; Male; Pyridines; Sodium Channel Blockers; Swine; Time Factors; Treatment Outcome; Triazoles; Ventricular Fibrillation

Previous studies have shown that late sodium channel current (INa) blockers such as ranolazine can exert antiarrhythmic effects by suppressing early and delayed afterdepolarization (EAD and DAD)-induced triggered activity.. To evaluate the electrophysiological properties of GS-458967 (GS967), a potent and highly selective late INa blocker, in canine Purkinje fibers (PFs) and pulmonary vein (PV) and superior vena cava (SVC) sleeve preparations.. Transmembrane action potentials were recorded from canine PFs and PV and SVC sleeve preparations by using standard microelectrode techniques. The rapidly activating delayed rectifier potassium channel current blocker E-4031 (2.5-5 µM) and the late INa agonist ATX-II (10 nM) were used to induce EADs in PFs. Isoproterenol (1 µM), high calcium ([Ca(2+)]o = 5.4 mM), or their combination was used to induce DADs and triggered activity.. In PFs, GS967 (10-300 nM) caused a significant concentration-dependent reduction in action potential duration without altering the maximum rate of rise of the action potential upstroke, action potential amplitude, or resting membrane potential at any rate studied (basic cycle lengths of 1000, 500, and 300 ms) or concentration evaluated (n = 5; P < .05). GS967 (30-100 nM) abolished EADs and EAD-induced triggered activity elicited in PFs by exposure to E-4031 (n = 4) or ATX-II (n = 4). In addition, GS967 reduced or abolished DADs and suppressed DAD-induced triggered activity elicited in PFs (n = 4) and PV (n = 4) and SVC (n = 3) sleeve preparations by exposure to isoproterenol, high calcium, or their combination.. Our data suggest that the selective inhibition of late INa with GS967 can exert antiarrhythmic effects by suppressing EAD- and DAD-mediated extrasystolic activity in PFs and PV and SVC sleeve preparations.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Disease Models, Animal; Dogs; Electrophysiological Phenomena; Heart Conduction System; Membrane Potentials; Pyridines; Sodium Channel Blockers; Triazoles