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BackgroundUremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).Methodology/Principal FindingsIn a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally 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 change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.Conclusions/SignificanceDPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

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We present an acoustic ejection mass spectrometry (AEMS) setup for ESI-MS based sample injection at a sampling rate faster than current ESI and MALDI techniques. A modified acoustic droplet ejection system was combined with an open port interface and a modified ESI source. To simulate applications of drug metabolism and pharmacokinetics analysis and high-throughput screening campaigns, two stress tests were performed regarding ion suppression and system endurance in combination with minor sample preparation. Maximum sampling rate was 6 Hz for dextromethorphan and d3-dextrorphan (each 100 nM) for 1152 injections in 63 s at FWHM of 105 ms and %RSD of 7.7%/7.5% without internal standard correction. Enzyme assay buffer and crude dog plasma caused signal suppression of 51%/73% at %RSD of 5.7%/6.7% (n = 120) and stable OPI performance during 1100 injections. An endurance buffer revealed minor OPI pollution and constant signals for >25.000 injections (%RSD = 8.5%, n = 10,557). File list (5) download file view on ChemRxiv Manuscript Ultrahigh-Throughput ESI-MS.pdf (0.94 MiB) download file view on ChemRxiv SI Ultrahigh-Throughput ESI-MS.pdf (2.59 MiB) download file view on ChemRxiv CC BY-NC-ND 4.0.url (54.00 B) download file view on ChemRxiv Video S-2.mp4 (17.97 MiB) download file view on ChemRxiv Video S-1.mp4 (6.04 MiB)