Effects of KR-32570, a new Na +/H + exchanger inhibitor, on functional and metabolic impairments produced by global ischemia and reperfusion in the perfused rat heart

Abstract

The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) on ischemia/reperfusion-induced mechanical and metabolic dysfunction in isolated rat hearts. In addition, the effects of KR-32570 on the Na +/H +-exchanger (NHE) and lipid peroxidation were also evaluated. KR-32570 strongly inhibited the recovery from acidosis induced by an NH 4Cl prepulse in PS120 fibroblast cells expressing the human NHE-1 isoform (IC 50: 0.05 and 1.16 μM for KR-32570 and cariporide, respectively). In isolated perfused rat hearts subjected to 30-min ischemia/30-min reperfusion, KR-32570 (1–10 μM) significantly and concentration dependently improved cardiac contractile function and severe contracture in conjunction with causing a marked reduction in lactate dehydrogenase release. Additionally, it (1–10 μM) significantly increased the content of ATP, creatine phosphate and glycogen as well as decreased the tissue lactate content in heart homogenates following ischemia and reperfusion. KR-32570 (1–10 μM) significantly decreased the concentration of 8- iso-prostaglandin F 2α, a reliable marker for oxidant stress, in perfusates from rat hearts subjected to ischemia and reperfusion. In separate experiments, KR-32570 significantly lowered the concentration of malondialdehyde in rat liver homogenate and inhibited Cu 2+-induced peroxidation of low-density lipoprotein. Taken together, these results suggest that KR-32570 possesses potent cardioprotective effects in perfused rat hearts, and its effects may be mediated by inhibition of NHE-1, preservation of high-energy phosphates, and inhibition of lipid peroxidation.