Anticonvulsant actions of furosemide in vitro.
Anticonvulsant properties of furosemide have been suggested to reduce neuronal synchronization via its inhibitory effect on the Na+/K+/2Cl- co-transport system. We have studied effects of furosemide on spontaneous epileptiform activity and analysed effects of furosemide on amplitudes of stimulus-induced population-spikes, on stimulus-induced K+ changes, on extracellular pH changes at rest and during stimulation, and on changes in the extracellular space-volume. We used three different in vitro models of epilepsy in the combined hippocampal-entorhinal cortex slice preparation. Furosemide reversibly suppressed low Ca2+-induced epileptiform activity in hippocampus proper and blocked or significantly reduced different types of epileptiform discharges in the low Mg2+ model and the 4-aminopyridine model. Amplitudes of evoked field potentials underwent an initial slight increase followed by a significant reduction after prolonged treatment with furosemide. Stimulus-induced increases in extracellular potassium were also significantly reduced. Furosemide caused an alkaline shift at rest. Stimulus-induced pH transients changed from a biphasic alkalotic-acidotic sequence to a monophasic alkalotic shift. Stimulation-induced shrinkage of extracellular space-volume was reduced by furosemide, whereas no effect on baseline extracellular space-volume was seen. We conclude, that furosemide possesses strong anticonvulsive effects in various in vitro models of epilepsy. The anticonvulsive properties of furosemide cannot be explained by its effects on extracellular pH changes but appear in part to be mediated via a reduced excitability with consequent reduction of activity-induced potassium rises. Finally, partial inhibition of activity-induced extracellular space shrinkage may contribute to its anticonvulsant properties.
Gutschmidt
K U
KU
Institut für Physiologie, Abt. Neurophysiologie, Universitätsklinikum Charité, Humboldt Universität zu Berlin, Germany.
Stenkamp
K
K
Buchheim
K
K
Heinemann
U
U
Meierkord
H
H
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000008:administration & dosage / Q000494:pharmacology; D004558:Electric Stimulation; D018728:Entorhinal Cortex / Q000503:physiopathology*; D004827:Epilepsy / Q000503:physiopathology*; D005260:Female; D005665:Furosemide / Q000494:pharmacology*; D006624:Hippocampus / Q000503:physiopathology*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008274:Magnesium / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009994:Osmolar Concentration; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019789:Tetraethylammonium / Q000378:metabolism
D000927:Anticonvulsants; D019789:Tetraethylammonium; D005665:Furosemide; D015761:4-Aminopyridine; D008274:Magnesium; D011188:Potassium; D002118:Calcium