Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy 英文参考文献.docVIP

EffectsofDPP-4InhibitorsontheHeartinaRatModelof UremicCardiomyopathy LyubovChaykovska1,2,KarolinevonWebsky1,2,JanRahnenfu¨hrer1,2,MarkusAlter1,2,3,SusiHeiden1,2 , HolgerFuchs4,FrankRunge4,ThomasKlein4,BertholdHocher1,2* 1Charite′ -Universita¨tsmedizin Berlin,CenterforCardiovascularResearch,InstituteforPharmacologyandToxicology,Berlin,Germany,2InstituteofNutritionalScience, University of Potsdam, Potsdam-Nuthetal, Germany, 3Charite′ - Universita¨tsmedizin Berlin, Medizinische Klinik fu¨r Endokrinologie und Nephrologie, Berlin, Germany, 4BoehringerIngelheimPharmaGmbHCo.KG,BiberachanderRiss,Germany Abstract Background: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-likepeptide-1(GLP-1)mayimprovecardiacfunction,butismainlydegradedbydipeptidylpeptidase-4(DPP-4). Methodology/PrincipalFindings:Inaratmodelofchronicrenalfailure,5/6-nephrectomized[5/6N]ratsweretreatedorally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant changeinbloodlevelAUC(0-‘)in5/6Nrats,butsitagliptinandalogliptinhadsignificantlyhigherAUC(0-‘)values;41%and 28%(p=0.0001andp=0.0324),respectively.NocorrelationofmarkersofrenaltubularandglomerularfunctionwithAUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 mmol/kg caused a 2-fold increaseinGLP-1(AUC201.0ng/l*h)in5/6Nratscomparedwithsham-treatedrats(AUC108.6ng/l*h)(p=0.01).ThemRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin. Conclusions/Significance:DPP-4inhibitionincreasesplasmaGLP-1levels,particularlyinuremia,andreducesexpressionof cardiacmRNAlevelsofmatrixproteinsandB-typenatriureticpeptides(BNP).Linagliptinmayofferauniqueapproachfor treatinguremiccardiomyopathyi