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 microM were 82 +/- 15% (p < 0.0001), and using tocainide 1 mM, 78 +/- 8% (p < 0.0001), with little suppression (< or = 10%) of the preanoxic response. Ajmaline (10-100 microM), disopyramide (10-300 microM) and bupivacaine (10-100 microM) were somewhat less effective, whereas verapamil produced 52 +/- 11% recovery before reduction of the preanoxic CAP was observed at 30 microM. Procainamide (100-300 microM) 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.
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Loeb Research Institute, Neuroscience Division, Ottawa Civic Hospital, University of Ottawa, Ontario, Canada.
D000200:Action Potentials / Q000187:drug effects; D000777:Anesthetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000134:cerebrospinal fluid / Q000494:pharmacology / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism*; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D026941:Sodium Channel Blockers
D000777:Anesthetics; D000889:Anti-Arrhythmia Agents; D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D002118:Calcium