Author + information
- Xiaoyan Liu,
- Ping Wang,
- Shandong Yu,
- Yanpeng Chu and
- Lin Wu
Late sodium current (INa,L) is increased in many pathological conditions, e.g., ischemic heart. Enhanced Na,L has been shown to elicit after-depolarizations and triggered arrhythmic activity. Eleclazine (GS-6615) has the properties of reducing INa,L in atrial and ventricular tissue and minimal effects on other ion channels, including peak INa, ICa,L, IKs and Ikr. The purpose of this study was to examine the effects of eleclazine on ventricular arrhythmias in hearts with acute global low-flow ischemia.
Hearts from New Zealand female rabbits were isolated and perfused in Langendorff mode with modified Krebs-Henseleit (K-H) solution warmed to 36.5-37°C, and was paced at 1 Hz. Monophasic action potentials (MAP) and pseudo 12-lead electrocardiograms (ECGs) were recorded. After an equilibration period of 30min with a constant flow rate of 20 ml/min, acute low-flow ischemia (15 min at 5.0 ml/min) was induced.
In the control hearts, flecainide (0.2-4μM) and ranolazine (2-10μM) significantly increased effective refractory period (ERP) and epi-MAPD90 of left ventricle in concentration dependent manners by 32.9±5.7%, 12.0±7.4% and 30.1±3.9%, 24.2±5.9%, respectively (n＝6, P<0.05), and thus led to an enhanced post-repolarization refractoriness (PRR) by 253.8±10.7% and 84.6±4.4% ms (P<0.05), respectively. Eleclazine (0.1-10μM) did not change ERP, Epi-MAPD90 and PPR (n＝6, P>0.05). No arrhythmia was observed. After 15min of low-flow ischemia, Epi-MAPD90 and QT interval were abbreviated significantly by -12.2±5.1% and -8.8±3.9%, respectively, (P<0.05), whereas transmural dispersion (TDR) and PPR were prolonged (34.6±7.3% and 16.2±5.9%, respectively, P<0.05) in all 23 hearts. Ischemia induced ventricular arrhythmias (ISC-VAs, ventricular tachycardia and ventricular fibrillation, VT/VF) occurred in 14/23 (60.9%). Flecainide prolonged ERP, Epi-MAPD90, PPR, TDR and QT interval in ischemia heart significantly, by 30.8±6.2%, 20.9±5.7%, 250.0±9.8%, 51.4±5.1% and 3.2±3.1% (n=7, P<0.05). Ranolazine prolonged ERP, Epi-MAPD90 and PPR, but reduced TDR by 27.7±4.9%, 22.1±5.2%, 187.5±7.7%, and -20±7.1%, respectively (n=8, P<0.05). Eleclazine decreased ERP, Epi-MAPD90, TDR and QT interval moderately (-4.1±2.9%, -4.3±3.0%, -11.7±5.5% and 1.6±1.2%, n=8, P<0.05), without effecting PPR (12.0±4.3%, P>0.05). Flecainide increased the incidence of ISC-VAs significantly (from 57.1% to 100%). Compared to ranolazine (from 62.5% to 37.5%), eleclazine caused greater reduction in ISC-VAs (from 62.5% to 25%, p<0.05).
Selective INa,L inhibition by eleclazine has no effect on ERP, Epi-MAPD90 and PPR in both control and ischemia condition, and exerts a potent protective effect against ISC-VAs. In contrast, flecainide and ranolazine increased proarrhythmic parameters, such as TDR and PPR, and ISC-VAs during acute low-flow ischemia.