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 NH(4)Cl prepulse in PS120 fibroblast cells expressing the human NHE-1 isoform (IC(50): 0.05 and 1.16 microM for KR-32570 and cariporide, respectively). In isolated perfused rat hearts subjected to 30-min ischemia/30-min reperfusion, KR-32570 (1-10 microM) 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 microM) 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 microM) significantly decreased the concentration of 8-iso-prostaglandin F(2 alpha), 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.
Lee
Byung Ho
BH
Medicinal Science Division, Korea Research Institute of Chemical Technology, #100, Jang-dong, Yusong, Taejon 305-343, Republic of Korea. bhlee@krict.re.kr
Seo
Ho Won
HW
Yi
Kyu Yang
KY
Lee
Sunkyung
S
Lee
Sunghou
S
Yoo
Sung-eun
SE
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002460:Cell Line; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010477:Perfusion; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D002316:Cardiotonic Agents; D006146:Guanidines; D008077:Lipoproteins, LDL; D017923:Sodium-Hydrogen Exchangers; D010725:Phosphocreatine; C075750:8-epi-prostaglandin F2alpha; C502305:(5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine; D008315:Malondialdehyde; D000255:Adenosine Triphosphate; D015237:Dinoprost