Amiodarone reduces depolarization-evoked glutamate release from hippocampual synaptosomes.
Decreased brain glutamate level has emerged as a new therapeutic approach for epilepsy. This study investigated the effect and mechanism of amiodarone, an anti-arrhythmic drug with antiepileptic activity, on glutamate release in the rat hippocampus. In a synaptosomal preparation, amiodarone reduced 4-aminopyridine-evoked Ca2+-dependent glutamate release and cytosolic Ca2+concentration elevation. Amiodarone did not affect the 4-aminopyridine-evoked depolarization of the synaptosomal membrane potential or the Na+channel activator veratridine-evoked glutamate release, indicating that the amiodarone-mediated inhibition of glutamate release is not caused by a decrease in synaptosomal excitability. The inhibitory effect of amiodarone on 4-aminopyridine-evoked glutamate release was markedly decreased in synaptosomes pretreated with the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, the calmodulin antagonists W7 and calmidazolium, or the protein kinase A inhibitors H89 and KT5720. However, the intracellular Ca2+-release inhibitors dantrolene and CGP37157 had no effect on the amiodarone-mediated inhibition of glutamate release. Furthermore, amiodarone reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that amiodarone reduces Ca2+influx through N- and P/Q-type Ca2+channels, subsequently reducing the Ca2+-calmodulin/protein kinase A cascade to inhibit the evoked glutamate release from rat hippocampal nerve terminals.
Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan.
Chia Yu
CY
Chang
School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chi Feng
CF
Hung
Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City, Taiwan.
Shu Kuei
SK
Huang
Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan.
Jinn Rung
JR
Kuo
School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan City, Taiwan. Electronic address: med0003@mail.fju.edu.tw.
Su Jane
SJ
Wang
D015761:4-Aminopyridine / Q000494:pharmacology; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001224:Aspartic Acid / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002211:Capsaicin / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020960:omega-Conotoxins / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002147:Calmodulin; D002227:Carbazoles; D007093:Imidazoles; D007546:Isoquinolines; D018942:Macrolides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; C120673:benzyloxyaspartate; D020960:omega-Conotoxins; D001224:Aspartic Acid; D018698:Glutamic Acid; C031938:calmidazolium; C057416:KT 5720; C017967:W 7; C040929:bafilomycin A1; D015761:4-Aminopyridine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000638:Amiodarone; D002211:Capsaicin; D002118:Calcium
Amiodarone; Ca(2+) channels; Glutamate release; Hippocampus; Synaptosomes