Inhibition of Na(+)/Ca(2+) exchange by KB-R7943, a novel selective antagonist, attenuates phosphoethanolamine and free fatty acid efflux in rat cerebral cortex during ischemia-reperfusion injury.
Reversal of the Na(+)/Ca(2+) exchanger (NCX) occurs during ischemia-reperfusion injury as a result of changes in intracellular pH and sodium concentration. Inhibition of NCXs has been shown to be neuroprotective in vitro. In this study, we evaluated the effects of KB-R7943 (50 microM), a specific inhibitor of the reverse mode of NCX, applied topically onto rat cerebral cortex prior to and during ischemia. Amino acid and free fatty acid levels in cortical superfusates, withdrawn at 10-min intervals from bilateral cortical windows, were analyzed by high-performance liquid chromatography. During a 20-min period of ischemia in control animals, there were significant increases in all amino acids and in all FFAs. Following reperfusion, all FFAs remained significantly elevated. Application of KB-R7943 (50 microM) significantly inhibited effluxes of phosphoethanolamine, but had no effect on glutamate, aspartate, taurine or GABA levels. KB-R7943 also resulted in significant reductions in levels of myristic, docosahexaenoic and arachidonic acid during ischemia and in reperfusion levels of arachidonic and docosahexaenoic acids. These data indicate that inhibition of Na(+)/Ca(2+) exchange likely prevented the activation of phospholipases that usually occurs following an ischemic insult as evidenced by its attenuation of phosphoethanolamine and free fatty acid efflux. The inhibition of phospholipases may be an essential component of the neuroprotective benefits of Na(+)/Ca(2+) exchange inhibitors in ischemia-reperfusion injury and may provide a basis for their possible use in therapeutic strategies for stroke.
Pilitsis
J G
JG
Department of Neurosurgery, Wayne State University, School of Medicine, UHC-6E, 4201 St. Antoine, Detroit, MI 48201, USA.
Diaz
F G
FG
O'Regan
M H
MH
Phillis
J W
JW
D000596:Amino Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000596:Amino Acids; D000889:Anti-Arrhythmia Agents; D004983:Ethanolamines; D005230:Fatty Acids, Nonesterified; D018696:Neuroprotective Agents; D019831:Sodium-Calcium Exchanger; C005448:phosphorylethanolamine; D010741:Phospholipases A; D013890:Thiourea