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

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 NH4Cl prepulse in PS120 fibroblast cells expressing the human NHE-1 isoform (IC50: 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 F2α, 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 Cu2+-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.