Abstract
The effects of the anticonvulsant diphenylhydantoin on the distribution of electrolytes and on radiosodium movement between plasma, brain and other tissues have been investigated in normal and acutely hyponatremic rats, and in rats subjected to maximal (tonic-clonic) electroshock seizures. The observed changes have been correlated with the effect of the drug on brain excitability as measured by the electroshock seizure threshold (EST) technic. The results obtained were as follows:
Diphenythydantoin (40 mgm./kgm., injected subcutaneously every 6 hours for four doses) elevated electroshock seizure threshold of normal animals by 17 per cent and prevented the marked decrease in EST induced by acute hyponatremia.
In normal rats, diphenythydantoin decreased both the total and the intracellular concentration of brain Na and increased the rate of movement of radiosodium into and out of brain cells. The ratio of extracellular to intracellular brain Na was increased. The drug also decreased intracellular Na concentration in skeletal and cardiac muscle, but to a lesser extent than in brain. Acutely induced hyponatremia was associated with an increase in intracellular brain Na concentration and a decrease in intracellular brain K concentration; these changes were largely prevented by treatment with diphenylhydantoin.
Plasma Na concentration of rats was increased one minute, and intracellular brain Na concentration was increased 5 minutes, after a maximal electroshock seizure. Brain K concentration was little changed following such a seizure. Diphenylhydantoin, in a dose sufficient to alter the maximal seizure to a purely clonic convulsion, not only prevented the increase in intracellular brain Na concentration but decreased the concentration below normal.
A direct correlation was found between the ratio of extracellular to intracellular brain Na concentration and the electroshock seizure threshold. No correlation was observed between the ratio of intracellular to extracellular brain K concentration and electroshock seizure threshold. The findings are interpreted to indicate that diphenythydantoin acts to suppress or modify convulsions by stimulating metabolic processes involved in the active extrusion of Na from brain cells and thereby decreases their susceptibility to seizure-activating processes.
Footnotes
- Received May 7, 1955.
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