%0 Journal Article %A Michiko Oka %A Yoshinori Itoh %A Yojiro Ukai %T Preferential Inhibition by a Novel Na+/Ca2+ Channel Blocker NS-7 of Severe to Mild Hypoxic Injury in Rat Cerebrocortical Slices: A Possible Involvement of a Highly Voltage-Dependent Blockade of Ca2+ Channel %D 2000 %J Journal of Pharmacology and Experimental Therapeutics %P 522-529 %V 293 %N 2 %X The hypoxic injury was induced in rat cerebrocortical slices by the exposure to hypoxia for 45 min in the absence or presence of 3 mM glucose, followed by reoxygenation for 5 h. The injury was more pronounced in the absence of glucose (severe hypoxic injury) than in the presence of glucose (mild hypoxic injury). A novel Na+/Ca2+ channel blocker, NS-7 [4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride], at 3 to 30 μM inhibited preferentially the severe hypoxic injury, whereas MK-801, ω-conotoxin GVIA (ω-CTX), andNG-nitro-l-arginine methylester suppressed preferentially the mild hypoxic injury. The extracellular cyclic GMP formation, a marker of nitric oxide synthesis, was enhanced during hypoxia, although the extent was greater in the absence of glucose. As observed in the hypoxic injury, NS-7 preferentially inhibited the cyclic GMP formation induced by severe hypoxic insults, whereas MK-801 or ω-CTX reduced it under mild hypoxic condition. When 30 to 50 mM KCl was applied to normoxic slices, a concentration-dependent increase in the extracellular cyclic GMP formation was observed. NS-7 blocked the cyclic GMP formation induced by 50 mM KCl but not by 30 to 40 mM KCl, whereas ω-CTX suppressed only the 30 mM KCl-evoked response. In primary neuronal culture, NS-7 reversed KCl-induced increase in intracellular Ca2+ in which the inhibition was marked when the KCl concentration was increased. These findings suggest that NS-7, unlike other neuroprotective compounds used in this study, is more effective in severe hypoxic injury. The highly voltage-dependent Ca2+channel blockade may contribute to the mode of neuroprotective action of NS-7. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/293/2/522.full.pdf