Effect of Na-K exchanger inhibitor bepridil on neuronal death -single fiber study-

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Neuronal death is a consequence of abnormal Ca influx into the cell. This Ca influx is caused by reverse operation of Na-Ca exchanger, which normally excretes calcium in exchange of sodium out of the cell. Recent report suggested a protective effect of Na-K exchanger inhibitors on ischemic neuronal death through preventing the reverse operation (Stys 1991, Ann Neurol 30 : 375). We examined the effect of bepridil, a inhibitor, on the conduction disturbance in a single fiber recording caused by ischemia. Twelve Wistar rats were anesthetized with pentobarbital and had laminectomy over the lower thoracic and lumber spines. After cutting the dura, we made a pool of paraffin over the cauda equina and picked up ventral roots from the tail. A root was hung over a pair of microelectrocles to record a single fiber action potential by stimulating the tail(Figure below). After having made a stable recording, we ligated the proximal end of the root to produce ischemia. Recording were made every minutes, and the procedures were reproduced applying a normal saline or bepridil (0.1 M) over the entire distal stump of the root in order to observe their specific effects. All the 21 fibers treated with saline from 12 rats showed conduction failure by 32 minutes after ligation (mean 22.8(〕SY.+-.〔)4.1). There was however no significant difference between normal saline-treated group and bepridil-treated group (mean 21.1(〕SY.+-.〔)5.2, n=14). The present study did not reveal any beneficial effect of the Na-K exchanger in contrast to the previous reoprt (Stys et al 1991). The difference may be accounted for by two factors. First, ischemic conduction disturbance may be overshadowed by depolarization brought about through suppression of the sodium potassium pump, which normally hyperpolarizes the membrane. Second, bepridil may have other actions than inhibiting the exchanger. Whatever the reason may be, bepridil may not warrant its further clinical trials for ischemic nervous system disorders