Cardioprotective Effects of KR-30450, a Novel K^+_<ATP> Opener, and Its Major Metabolite KR-30818 on Isolated Rat Hearts

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The cardiac effects of KR-30450 ((-)-(2<I>R</I>)-2-([1, 3]-dioxolan-2-yl)-2-methyl-4-(2-oxopyrrolidin-1-yl)-6-nitro-2<I>H</I>-1-benzopyran), a newly synthesized potassium channel activator, and its major metabolite KR-30818 ((-)-(2<I>R</I>)-2-hydroxymethyl-2-methyl-4-(2-oxopyrrolidin-1-yl)-6-nitro-2<I>H</I>-1-benzopyran) were compared with those of lemakalim, a prototype of this class, in isolated globally ischemic rat hearts. KR-30450 and KR-30818 significantly improved reperfusion cardiac function (LVDP, left ventricular developed pressure; double product, LVDP×heart rate/1000), their potency being 5.2-fold and 0.7-fold greater than lemakalim (ED<SUB>50</SUB> for recovering predrug double product: 0.10, 0.80 and 0.54 μM, respectively). KR-30450 and KR-30818 significantly attenuated reperfusion contracture and lactate dehydrogenase release with potency greater than and equal to lemakalim, respectively. They significantly increased time to contracture (TTC) during ischemia in a dose-dependent manner with a greater potency than lemakalim (EC<SUB>25</SUB> for increasing TTC: 1.2, 2.1 and 3.2 μM, respectively). The protective effects of three compounds on the measured parameters were reversed by glyburide, a selective K<SUP>+</SUP><SUB>ATP</SUB> blocker. In non-ischemic hearts, KR-30450 and lemakalim exerted weak negative inotropism at high concentrations and KR-30818 had no effects, whereas the three compounds significantly increased coronary flow at doses studied. Glyburide completely reversed preischemic cardiodepressant effects of these compounds but not their effects on coronary flow. In conclusion, KR-30450, a recently developed K<SUP>+</SUP><SUB>ATP</SUB> opener, exerted more potent cardioprotective effects than lemakalim, and its major metabolite KR-30818 may play a significant role in its action in vivo.

収録刊行物

  • The Japanese journal of pharmacology

    The Japanese journal of pharmacology 76(1), 65-73, 1998-01

    公益社団法人 日本薬理学会

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各種コード

  • NII論文ID(NAID)
    10008191151
  • NII書誌ID(NCID)
    AA00691188
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    00215198
  • NDL 記事登録ID
    4395859
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  CJP引用  NDL  J-STAGE 
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