The cardioprotective effects of
KR-31761, a newly synthesized K+(
ATP) opener, were evaluated in rat models of
ischemia/reperfusion (I/R)
heart injury. In isolated rat hearts subjected to 30-min global
ischemia/30-min reperfusion,
KR-31761 perfused prior to
ischemia significantly increased both the left ventricular developed pressure (% of predrug LVDP: 17.8, 45.1, 54.2, and 62.6 for the control, 1 microM, 3 microM, and 10 microM, respectively) and double product (DP: heart rate x LVDP; % of predrug DP: 17.5, 44.9, 56.2, and 64.5 for the control, 1 microM, 3 microM, and 10 microM, respectively) at 30-min reperfusion while decreasing the left ventricular end-diastolic pressure (LVEDP).
KR-31761 (10 microM) significantly increased the time to
contracture during the ischemic period, whereas it concentration-dependently decreased the
lactate dehydrogenase release during reperfusion. All these parameters were significantly reversed by
5-hydroxydecanoate (5-HD, 100 microM) and
glyburide (1 microM), selective and nonselective blockers of the mitochondrial K+(
ATP) (
mitoK+(ATP)) channel and K+(
ATP) channel, respectively. In anesthetized rats subjected to 30-min occlusion of left anterior descending coronary artery/2.5-h reperfusion,
KR-31761 administered 15 min before the onset of
ischemia significantly decreased the
infarct size (72.2%, 55.1%, and 47.1% for the control, 0.3 mg/kg, i.v., and 1.0 mg/kg, i.v., respectively); and these effects were completely and almost completely abolished by 5-HD (10 mg/kg, i.v.) and
HMR-1098, a selective blocker of sarcolemmal K+(
ATP) (sarcK+(
ATP)) channel (6 mg/kg, i.v.) administered 5 min prior to
KR-31761 (72.3% and 67.9%, respectively).
KR-31761 only slightly relaxed
methoxamine-precontracted rat aorta (IC50: > 30.0 microM). These results suggest that
KR-31761 exerts potent cardioprotective effects through the opening of both
mitoK+(ATP) and sarcK+(
ATP) channels in rat hearts with a minimal
vasorelaxant effect.