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-nitr o-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.