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Research ArticleNEUROPHARMACOLOGY

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

Michiko Oka, Yoshinori Itoh and Yojiro Ukai
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 522-529;
Michiko Oka
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Yoshinori Itoh
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Yojiro Ukai
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Abstract

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.

Footnotes

  • Send reprint requests to: Michiko Oka, Research Laboratories, Nippon Shinyaku Co., Ltd., Nishiohji Hachijo Minami-ku, Kyoto 601, Japan. E-mail: m.oka{at}po.nippon-shinyaku.co.jp

  • Abbreviations:
    NOS
    nitric-oxide synthase
    LDH
    lactate dehydrogenase
    [Ca2+]i
    intracellular free Ca2+ concentration
    KRB
    Krebs-Ringer- bicarbonate solution
    NO
    nitric oxide
    NS-7
    4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride
    ω-CTX
    ω-conotoxin GVIA
    ω-Aga
    ω-agatoxin IVA
    l-NAME
    NG-nitro-l-arginine methylester
    DMEM
    Dulbecco's modified Eagle's minimum essential medium
    BAPTA/AM
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid/acetoxymethyl ester
    IBMX
    3-isobutyl-1-methylxanthine
    NMDA
    N-methyl-d-aspartate
    • Received October 12, 1999.
    • Accepted January 20, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleNEUROPHARMACOLOGY

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

Michiko Oka, Yoshinori Itoh and Yojiro Ukai
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 522-529;

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Research ArticleNEUROPHARMACOLOGY

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

Michiko Oka, Yoshinori Itoh and Yojiro Ukai
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 522-529;
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