Abstract: AimTo investigate the effect of iptakalim (Ipt), a novel ATP-sensitive potassium channel opener (KATPCO), on astrocyte glutamate uptake activity. The mechanism of action involved was also examined. MethodsPrimary cultures of astrocytes were prepared from cerebral cortexes of 1 to 2 days old Sprague-Dawley rats. Cultures were preincubated with iptakalim of various concentrations with the absence or presence of 6-hydroxydopamine (6-OHDA, 50 μmol·L^-1). Then, the cells were treated with pinacidil (10 μmol·L^-1, K⁺ channel opener) instead of iptakalim and pretreated with glibenclamide (20 μmol·L^-1, ATP-sensitive K⁺ channel inhibitor) before pinacidil or iptakalim was added into the medium so that the mechanism of action of iptakalim could be analysed. Astrocyte glutamate uptake activity was determined by intracellular concentration of ³H labeled D,L-glutamate, using isotope techniques. Results Both iptakalim and pinacidil were shown to increase glutamate uptake activity of astrocytes and reverse inhibitory effect induced by 6-OHDA. But the increased and reversed effects of iptakalim or pinacidil on astrocytic glutamate uptake were found to be completely antagonized by glibenclamide. ConclusionThese data indicated that iptakalim can enhance astrocytic glutamate uptake activity due to its K⁺ channel opening properties and lessen glutamate excitotoxicity. Iptakalim may be useful for the therapy of Parkinson′s disease.