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Original Article

Korean Journal of Physiology and Pharmacology 2018; 22(6): 713-719

Published online November 1, 2018 https://doi.org/10.4196/kjpp.2018.22.6.713

Copyright © The Korean Journal of Physiology & Pharmacology.

Potentiation of endothelium-dependent vasorelaxation of mesenteric arteries from spontaneously hypertensive rats by gemigliptin, a dipeptidyl peptidase-4 inhibitor class of anti-diabetic drug

Hae Jin Kim1,2, Eun Bok Baek3,*, and Sung Joon Kim1,2,*

1Department of Physiology, 2Hypoxic/Ischemic Disease Institute, Seoul National University College of Medicine, Seoul 03080, 3Department of Regulatory Toxi-cology, Life Science R&D, LG Chem Ltd., LG Science Park, Seoul 07796, Korea

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Dipeptidyl peptidase4 (DPP4) inhibitors such as gemigliptin are anti-diabetic drugs elevating plasma concentration of incretins such as GLP-1. In addition to the DPP4 inhibition, gemigliptin might directly improve the functions of vessels under pathological conditions. To test this hypothesis, we investigated whether the acetylcholine-induced endothelium dependent relaxation (ACh-EDR) of mesenteric arteries (MA) are altered by gemigliptin pretreatment in Spontaneous Hypertensive Rats (SHR) and in Wistar-Kyoto rats (WKY) under hyperglycemia-like conditions (HG; 2 hr incubation with 50 mM glucose). ACh-EDR of WKY was reduced by the HG condition, which was significantly recovered by 1 μM gemigliptin while not by saxagliptin and sitagliptin up to 10 μM. The ACh-EDR of SHR MA was also improved by 1 μM gemigliptin while similar recovery was observed with higher concentration (10 μM) of saxagliptin and sitagliptin. The facilitation of ACh-EDR by gemigliptin in SHR was not observed under pretreatment with NOS inhibitor, L-NAME. In the endothelium-denuded MA of SHR, sodium nitroprusside induced dose-dependent relaxation was not affected by gemigliptin. The ACh-EDR in WKY was decreased by treatment with 30 μM pyrogallol, a superoxide generator, which was not prevented by gemigliptin. Exendin-4, a GLP-1 analogue, could not enhance the ACh-EDR in SHR MA. The present results of ex vivo study suggest that gemigliptin enhances the NOS-mediated EDR of the HG-treated MA as well as the MA from SHR via GLP-1 receptor independent mechanism.

Keywords: Dipeptidyl peptidase-4, Endothelium dependent relaxation, Gemigliptin, Hypertension, Hyperglycemia