Table 5.
Late Ina inhibition and antiarrhythmic properties
| Model | Inhibitor | Inhibitor administration | Dose | Effect | Author |
|---|---|---|---|---|---|
| Langendorff perfused rat hearts (rapid pacing induced VF and oxidative stress induced VF) | Ranolazine | Prior to challenge | 10 μM |
Pacing induced VF shortening >3 min → 12 ± 6 s Oxidative stress induced VF termination and suppression |
Morita 2011 [77] |
| Transgenic CaMKII mice papillary muscles | Ranolazine | After challenge | 5 μmol/L | Termination of premature arrhythmogenic contractions | Sossalla 2011 [78] |
| CAVB dog, dofetilide induced | Ranolazine | After challenge | 4 mg/kg/0.5 min + 0.225 mg/kg/min | TdP episodes ↓ 10 → 3 | Antoons 2010 [79] |
| In vivo animal model (rats I/R induced arrhythmias and ischemia induced arrhythmias) | Ranolazine |
After challenge (I/R) Prior to challenge (I) |
10 mg/kg iv bolus (I/R) 2, 6, 10 μM (I and I/R) |
Sustained VT incidence ↓ 9/12 vs. 1/11 (I/R) VF incidence ↓ 10/12, 8/12, 5/10, 4/12 (control, 2, 8, 10 μM Ranolazine resp.) |
Dhalla 2009 [80] |
| Clinical trial | Ranolazine | Prior to challenge | Reduced the incidence of VT vs placebo | Scirica 2007 [81] | |
| Rabbit and guinea pig isolated ventricular myocytes H2O2 challenge | Ranolazine | After challenge | 10 μM | Suppression of APD prolongation and EAD formation | Song 2006 [82] |
| Canine myocytes of normal and HF dogs | Ranolazine | After challenge | 5, 10, 20 μM | Shortening of APD and suppression of EADs | Undrovinas 2006 [83] |
| Langendorff perfused guinea pig hearts. ATX-II induced arrhythmias | Ranolazine | Both | 5 μM | Ranolazine abolished ATX-II induced EADs/VTs and prevented ATX-II induced EADs/VTs in pretreated hearts | Wu 2004 [84] |
| Langendorff perfused rat hearts I/R ATX-II challenge | Ranolazine | Prior to challenge | 4 μM, 9 μM in perfusate | Reduced Ca2+ overload and LV mechanical dysfunction | Fraser 2006 [85] |
| Isolated canine wedge preparations, M cells and Purkinje fibres | Ranolazine | Prior to challenge | 1–100 μmol/L | Abolished TdP and EADs | Antzelevitch 2004 [76] |
| Isolated guinea pig ventricular myocytes–ATX-II challenge | Ranolazine | After challenge | 0.1–30 μmol/L | Reduced ATX-II induced EADs | Song 2004 [86] |
| Canine Purkinje fibres E-4031, ATX-II and high Ca+ isoproterenol induction | GS-967 | After challenge | 30 nM/100 nM |
EAD and DAD incidence ↓ EAD 4/4 → 2/5 → 0/5 (E-4031) EAD 4/4 → 1/4 → 0/4 (ATX-II) DAD 4/4 → 2/4 → 0/5 (high Ca+ isoproterenol) |
Sicouri et al. 2013 [87] |
| Langendorff perfused rabbit heart ATX-II and E-4031 induction | GS-967 | After challenge | 100 and 600 nmol/L (ATX-II and E-4031 resp.) | Incidence of VT ↓ 6/11 → 0/11 (ATX-II) 5/5 → 0/5 (E-4031) | Belardinelli et al. 2013 [88] |
| In vivo animal model (rabbits clofilium/methoxamine and ischaemia induced) | GS-967 | Prior to challenge |
60 μg/kg bolus + 16 μg/kg/min (clofilium) 15 μg/kg + 4 μg/kg/min (ischaemia) |
Incidence VT ↓ 5/6 → 1/6 (clofilium) 5/10 → 2/8 (ischemia) | Belardinelli et al. 2013 [88] |
| Langendorff perfused guinea pig heart isoprenaline induction | Sophocarpine | After challenge | 300 μmol/L | incidence VT ↓ 6/6 → 0/6 | Yang et al. 2011 [89] |
EAD early after depolarisation. TdP torsade de pointes arrhythmia. I/R ischaemia reperfusion model. VT ventricular tachycardia. A H2O2 challenge mimics oxidative stress