Ys. Jung et al., CARDIOPROTECTIVE EFFECTS OF KR-30450, A NOVEL K-ATP(-30818 ON ISOLATED RAT HEARTS() OPENER, AND ITS MAJOR METABOLITE KR), Japanese Journal of Pharmacology, 76(1), 1998, pp. 65-73
The cardiac effects of KR-30450 4-(2-oxopyrrolidin-1-yl)-6-nitro-2H-1-
benzopyran), a newly synthesized potassium channel activator, and its
major metabolite KR-30818 -4-(2-oxopyrrolidin-1-yl)-6-nitro-2H-1-benzo
pyran) were compared with those of lemakalim, a prototype of this clas
s, in isolated globally ischemic rat hearts. KR-30450 and KR-30818 sig
nificantly improved reperfusion cardiac function (LVDP, left ventricul
ar developed pressure; double product, LVDP x heart rate/1000), their
potency being 5.2-fold and 0.7-fold greater than lemakalim (ED50 for r
ecovering predrug double product: 0.10, 0.80 and 0.54 mu M, respective
ly). KR-30450 and KR-30818 significantly attenuated reperfusion contra
cture 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 g
reater potency than lemakalim (EC25 for increasing TTC: 1.2, 2.1 and 3
.2 mu M, respectively). The protective effects of three compounds on t
he 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 effect
s, whereas the three compounds significantly increased coronary flow a
t doses studied. Glyburide completely reversed preischemic cardiodepre
ssant effects of these compounds but not their effects on coronary flo
w. In conclusion, KR-30450, a recently developed K-ATP(+) opener, exer
ted more potent cardioprotective effects than lemakalim, and its major
metabolite KR-30818 may play a significant role in its action in vivo
.