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

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 × 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.