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In this study, the effects of ursodeoxycholic acid (UDCA) on ischemia/reperfusion injury were investigated on isolated heart perfusion model. Hearts were perfused with oxygenated Krebs-Henseleit solution (pH 7.4, 37 degrees C) on a Langendorff apparatus. After equilibration, isolated hearts were treated with UDCA 20 to 160 microM or vehicle (0.04% DMSO) for 10 min before the onset of ischemia. After global ischemia (30 min), ischemic hearts were reperfused and allowed to recover for 30 min. The physiological (i.e. heart rate, left ventricular developed pressure, coronary flow, double product and time to contracture formation) and biochemical (lactate dehydrogenase; LDH) parameters were evaluated. In vehicle-treated group, time to contracture formation was 21.4 min during ischemia, LVDP was 18.5 mmHg at the endpoint of reperfusion and LDH activity in total reperfusion effluent was 54.0 U/L. Cardioprotective effects of UDCA against ischemia/reperfusion consisted of a reduced TTC (EC25=97.3 microM), reduced LDH release and enhanced recovery of cardiac contractile function during reperfusion. Especially, the treatments of UDCA 80 and 160 microM significantly increased LVDP and reduced LDH release. Our findings suggest that UDCA ameliorates ischemia/reperfusion-induced myocardial damage.

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.

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