Inhibition of Na+/Ca2+ 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+ 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 muM), a specific inhibitor of the reverse mode of NCX, applied topically onto rat cerebral cortex prio r to and during ischemia. Amino acid and free fatty acid levels in cortical superfusates, withdrawn at 10-min intervals from bilateral cortical window s, were analyzed by high-performance liquid chromatography.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 muM) significantly inhi bited effluxes of phosphoethanolamine, but had no effect on glutamate, aspa rtate, taurine or GABA levels. KB-R7943 also resulted in significant reduct ions in levels of myristic, docosahexaenoic and arachidonic acid during isc hemia and in reperfusion levels of arachidonic and docosahexaenoic acids. T hese data indicate that inhibition of Na+/Ca2+ exchange likely prevented th e activation of phospholipases that usually occurs following an ischemic in sult 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+/Ca2+ exchange inhibitors in ischemi a-reperfusion injury and may provide a basis for their possible use in ther apeutic strategies for stroke. (C) 2001 Elsevier Science B.V. All rights re served.