Protective Effects of Antiarrhythmic Agents against Anoxic Injury in CNS White Matter

Irreversible anoxic injury is dependent on extracellular Ca²⁺ in mammalian CNS white matter, with a large portion of the pathologic Ca²⁺ influx occurring through reverse Na⁺ –Ca²⁺ exchange, stimulated by increased intracellular [Na⁺]. This Na⁺ leak likely occurs via incompletely inactivated voltage-gated Na⁺ channels. This study reports that clinically used antiarrhythmic compounds, likely by virtue of their Na⁺ channel– blocking properties, significantly protect CNS white matter from anoxia at concentrations that cause little suppression of the preanoxic response. Rat optic nerves were pretreated with various agents for 60 min, then subjected to 60 min of anoxia in vitro. Functional recovery was measured electrophysiologically as the area under the compound action potential (CAP). Without drug, the CAP areas recovered to a mean of 32 ± 12% of control after 1 h of reoxygenation. Recoveries using prajmaline 10 μM were 82 ± 15% (p < 0.0001), and using tocainide 1 mM, 78 ± 8% (p < 0.0001), with little suppression (≤10%) of the preanoxic response. Ajmaline (10–100 μM), disopyramide (10–300 μM) and bupivacaine (10–100 μM) were somewhat less effective, whereas verapamil produced 52 ± 11% recovery before reduction of the preanoxic CAP was observed at 30 μM. Procainamide (100– 300 μM) was ineffective. These results suggest that Na⁺ channel blockers, including commonly used antiarrhythmic agents, may be effective in protecting central white matter, which is a target for anoxic/ischemic injury in diseases such as stroke and spinal cord injury.