The Persistent Sodium Current Blocker Riluzole Is Antiarrhythmic and Anti-Ischaemic in a Pig Model of Acute Myocardial Infarction

Abstract

BackgroundThe potential of the cardiac persistent sodium current as a target for protection of the myocardium from ischaemia and reperfusion injury is gaining increasing interest. We have investigated the anti-ischaemic and antiarrhythmic effects of riluzole, a selective INaP blocker, in an open chest pig model of infarction.Methods and Principal FindingsThe left anterior descending coronary artery (LAD) was ligated in 27 anesthetised pigs (landrace or large white, either sex, 20–35 kg) which had received riluzole (8 mg/kg IP; n = 6), lidocaine (2.5–12 mg/kg bolus plus 0.05–0.24 mg/kg/min; n = 11) or vehicle (n = 10) 50 min prior. Arrhythmias could be delineated into phase 1a (0 to 20 min), phase 1b (20 to 50 min) and phase 2 (from 50 min to termination at 180 min) and were classified as premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) (spontaneously reverting within 15 s) or sustained VT or VF (ie. requiring cardioversion at 15 s). Riluzole reduced the average number of all arrhythmias in Phase 2 (PVCs from 484+/−119 to 32+/−13; non sustained arrhythmias from 8.9+/−4.4 to 0.7+/−0.5; sustained arrhythmias from 3.9+/−2.2 to 0.5+/−0.4); lidocaine reduced the average number of non-sustained and sustained arrhythmias (to 0.4+/−0.3 and 0.4+/−0.3 respectively) but not PVCs (to 390+/−234). Riluzole and lidocaine reduced the average number of sustained arrhythmias in phase 1b (from 1.8+/−0.4 to 0.17+/−0.13 (p<0.02) and to 0.55+/−0.26 (p = ns) respectively). Neither lidocaine or riluzole changed the ECG intervals: there was no statistical significance between groups at time zero (just before ligation) for any ECG measure. During the course of the 3 hour period of the ischaemia R-R, and P-R intervals shortened slightly in control and riluzole groups (not significantly different from each other) but not in the lidocaine group (significantly different from control). QRS and QTc did not change appreciably in any group Riluzole reduced the degree of histopathological tissue damage across the infarct zone considerably more than did lidocaine.ConclusionsAt the doses used, riluzole was at least as effective as lidocaine at reducing the number of episodes of ischaemic VT or VF in pigs, and much more effective at reducing the number of PVCs. We propose that this is related to the ability of riluzole to block cardiac persistent sodium current.

Riluzole reduces arrhythmias and myocardial damage induced by coronary occlusion in anaesthetized pigs

“…Because I NaP is only approximately 0.5%–1% of the size of the transient sodium current ( I NaT ), block of I NaP would not be expected to materially affect the ECG intervals QRS, PR or Q‐Tc. We have reported previously, and confirmed in the present study, that riluzole does not affect any of these intervals at the dose used, reinforcing the relative selectivity of block of I NaP over I NaT .…”

“…Subsequently, we showed in a anaesthetized pig model that pretreatment with riluzole (8 mg/kg, i.p.) reduced arrhythmias and appeared to reduce gross myocardial damage following infarction . In the present study, we extended these experiments and investigated the effect of a brief intravenous infusion of riluzole (2 mg/kg, i.v.…”

Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury

“…Riluzole blocks Trpm4, but in a non-specific manner – many other targets are also blocked or inhibited by this drug. Riluzole blocks persistent sodium currents from channels typically not identified molecularly (Lamanauskas and Nistri, 2008; Lamas et al, 2009; Tazerart et al, 2007; Urbani and Belluzzi, 2000; Weiss and Saint, 2010; Xie et al, 2011). Riluzole blocks several molecularly identified potassium channels (Ahn et al, 2005; Cao et al, 2002; Duprat et al, 2000; Xu et al, 2001; Zona et al, 1998), and calcium channels (Huang et al, 1997; Siniscalchi et al, 1997; Stefani et al, 1997).…”

“…At micromolar concentrations (IC 50 ,3–10 μM), riluzole is considered to be a relatively selective blocker of “persistent sodium currents” in cardiac myocytes and CNS neurons, including spinal cord neurons, where the molecular identity of the channel(s) responsible for these currents is not known (Lamanauskas and Nistri, 2008; Lamas et al, 2009; Tazerart et al, 2007; Urbani and Belluzzi, 2000; Weiss and Saint, 2010; Xie et al, 2011). …”

Class I and III antiarrhythmic drugs for prevention of sudden cardiac death and management of postmyocardial infarction arrhythmias. A review

“…The increased interest in AADs is attested to by the testing of the antiarrhythmic efficacy of the known neuroprotective agents ranolazine and riluzole, i.e., agents blocking myocyte membrane-acting sodium channels 6,7 . Prevention and treatment of life-threatening ventricular arrhythmias have recently been improved by ICD placement.…”