Potassium channel blockers attenuate hypoxia- and ischemia-induced neuronal death in vitro and in vivo.
OBJECTIVE
In light of recent evidence suggesting that an upregulation of K+ efflux mediated by outward delayed rectifier (I(K)) channels promotes central neuronal apoptosis, we sought to test the possibility that blockers of I(K) channels might be neuroprotective against hypoxia/ischemia-induced neuronal death.


METHODS
Membrane currents were recorded with the use of patch clamp recordings in cultured murine cortical neurons. Protective effects of K+ channel blockers were examined in rats subjected to transient middle cerebral artery occlusion followed by 14-day reperfusion.


RESULTS
The K+ channel blocker tetraethylammonium (TEA) (5 mmol/L) selectively blocked I(K) without affecting N-methyl-D-aspartate receptor-mediated current or voltage-gated Ca2+ currents. Both TEA and a lipophilic K+ channel blocker, clofilium, attenuated neuronal apoptosis induced by hypoxia in vitro and infarct volume induced by ischemia in vivo.


CONCLUSIONS
These data are consistent with the idea that K+ channel-mediated K+ efflux may contribute to ischemia-triggered apoptosis and suggest that preventing excessive K+ efflux through K+ channels may constitute a therapeutic approach for the treatment of stroke.
Wei
Ling
L
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
Yu
Shan Ping
SP
Gottron
Frank
F
Snider
B Joy
BJ
Zipfel
Gregory J
GJ
Choi
Dennis W
DW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D017536:Carotid Artery, Common; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D002540:Cerebral Cortex / Q000166:cytology; D003470:Culture Media / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D017136:Ion Transport / Q000187:drug effects; D008026:Ligation; D008297:Male; D051379:Mice; D020768:Middle Cerebral Artery; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology*
D015220:Calcium Channels; D003470:Culture Media; D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D019789:Tetraethylammonium; C022799:clofilium; D005947:Glucose; D011188:Potassium; D002118:Calcium