Yi-Sook Jung (1,#), Chang-Hyun Moon (2), Tai-Soon Cho (3), Sung-Eun Yoo
(4) and Hwa-Sup Shin (1,#)
(1) Screening and Toxicology Research Center and (4) Bio-organic Division,
Korea Research Institute of Chemical Technology, (#) 100, Jang-dong, Yusong,
Taejeon 305-343, Korea
(2) Department of Physiology, School of Medicine, Ajou University, Suwon
441-749, Korea
(3) College of Pharmacy, Sung Kyun Kwan University, Suwon 440-746, Korea
(#) Present address: Department of Physiology, School of Medicine, Ajou
University, Suwon 441-749, Korea
(*) To whom correspondence should be addressed.
Abstract: 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 x 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 microM, 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 microM, 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.
Keywords: KR-30450 (SKP-450), KR-30818 (SKP-818), Lemakalim, Potassium
channel activator, Cardioprotection