Potassium channel blockers attenuate hypoxia- and ischemia-induced neuronal death in vitro and in vivo

Background and Purpose - 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.