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

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概要

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• The cardiac effects of KR-30450 ((-)-(2R)-2-([1, 3]-dioxolan-2-yl)-2-methyl-4-(2-oxopyrrolidin-1-yl)-6-nitro-2H-1-benzopyran), a newly synthesized potassium channel activator, and its major metabolite KR-30818 ((-)-(2R)-2-hydroxymethyl-2-methyl-4-(2-oxopyrrolidin-1-yl)-6-nitro-2H-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 (ED50 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 (EC25 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+ATP 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+ATP opener, exerted more potent cardioprotective effects than lemakalim, and its major metabolite KR-30818 may play a significant role in its action in vivo.

• 社団法人 日本薬理学会の論文

著者

• Moon Chang-hyun

  Department Of Physiology Ajou University School Of Medicine

• Moon C‐h

  Ajou Univ. Suwon Kor

• Yoo Sung-eun

  Medical Science Division Korea Research Institute Of Chemical Technology

• Yoo S‐e

  Korea Res. Inst. Of Chemical Technol. Daejon Kor

• Cho Tai-soon

  College Of Pharmacy Sung Kyun Kwan University

• Shin Hwa-sup

  Department Of Applied Biochemistry Division Of Life Science College Of Biomedical And Health Science

• Shin Hwa-sup

  Screening And Toxicology Research Center Korea Research Institute Of Chemical Technology

• JUNG Yi-Sook

  Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology

• YOO Sung-Eun

  Bio-organic Division, Korea Research Institute of Chemical Technology

• Jung Yi-sook

  Department Of Physiology Ajou University School Of Medicine

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