The persistent sodium current blocker riluzole is antiarrhythmic and anti-ischaemic in a pig model of acute myocardial infarction.

Abstract

BACKGROUND: The 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 FINDINGS: The 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. CONCLUSIONS: At 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.