Advances in Clinical and Experimental Medicine
2018, vol. 27, nr 11, November, p. 1483–1490
Publication type: original article
The impact of sitagliptin, inhibitor of dipeptidyl peptidase-4 (DPP-4), on the ADMA-DDAH-NO pathway in ischemic and reperfused rat livers
1 Department of Pharmacology, Faculty of Medicine, Wroclaw Medical University, Poland
2 Department of Internal Medicine, 4th Military Hospital with Policlinic, Wrocław, Poland
3 Department of Internal Nursing, Faculty of Health Sciences, Wroclaw Medical University, Poland
4 Department of Histology and Embryology, Faculty of Medicine, Wroclaw Medical University, Poland
5 Department of Histology and Embryology, Poznan University of Medical Sciences, Poland
6 Department of Medical Biochemistry, Faculty of Medicine, Wroclaw Medical University, Poland
7 Department of Epizootiology and Clinic of Bird and Exotic Animals, Wroclaw University of Environmental and Life Sciences, Poland
Background. A correlation between the level of asymmetric dimethylarginine (ADMA) – the inhibitor of the nitric oxide (NO) synthesis – and the liver function and survival after a liver transplantation has been reported.
Objectives. The aim of this study was to evaluate the effect of sitagliptin –the inhibitor of dipeptidyl peptidase-4 (DPP-4) – on the NO-ADMA-dimethylarginine dimethylaminohydrolase (DDAH) pathway in rat livers subjected to ischemia/reperfusion (IR).
Material and Methods. The rats received sitagliptin (5 mg/kg, per os – p.o.) (groups: S – livers not subjected to IR procedure, and SIR – livers subjected to IR procedure) or a saline solution (groups: C – livers not subjected to IR procedure, and CIR – livers subjected to IR procedure) for 14 days; following this, livers in the SIR and CIR groups were subjected to ischemia (60 min) and reperfusion (24 h). Aminotransferases were measured before the surgery; additionally, the arginine (ARG), ADMA and symmetric dimethylarginine (SDMA) levels were estimated just before ischemia and during reperfusion (at 0.5, 4 and 24 h). After IR, citrulline, the DDAH activity, mRNA for type 1 DDAH (DDAH1), and arginine methyltransferase type 1 (PRMT1) were determined.
Results. The increase in the initial level of ARG/ADMA0 (A/A) ratio in group S compared to group C verged on statistical significance. At 0.5 and 4 h of reperfusion, the highest concentration of ADMA was found in group CIR. At those time points, the ARG level and the A/A ratio were decreased in groups CIR and SIR as compared to groups C and S, respectively. The alanine transaminase (ALT) activity was lower in the sitagliptin-treated group than in the non-treated one. The DDAH and citrulline levels were reduced in group CIR as compared to group C, but were greater in group SIR as compared to group S. The PRMT1 mRNA expression was higher in groups CIR and SIR, compared to groups C and S, respectively.
Conclusion. The increased A/A ratio suggests a protective effect of sitagliptin on livers not subjected to IR. Changes in the DDAH activity and the PRMT1 mRNA expression also imply the protective activity of sitagliptin during IR.
liver, rat, ischemia/reperfusion, asymmetric dimethylarginine, sitagliptin
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