CARDIOPROTECTIVE EFFECTS OF KR-30450, A NOVEL K-ATP(-30818 ON ISOLATED RAT HEARTS() OPENER, AND ITS MAJOR METABOLITE KR)

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 .