The vasodilatory effect of gemigliptin via activation of voltage-dependent K + channels and SERCA pumps in aortic smooth muscle.

Autor: Jung HS; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Seo MS; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., An JR; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Kang M; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Heo R; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Li H; Institute of Translational Medicine, Medical College, Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment for Senile Diseases, Yangzhou University, Yangzhou, 225001, China., Jung WK; Department of Biomedical Engineering, And Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, 48513, South Korea., Choi IW; Department of Microbiology, Inje University College of Medicine, Busan, 48516, South Korea., Cho EH; Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Park H; Department of Urology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Bae YM; Department of Physiology, Konkuk University School of Medicine, Chungju, 27478, South Korea., Park WS; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea. Electronic address: parkws@kangwon.ac.kr.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2020 Sep 05; Vol. 882, pp. 173243. Date of Electronic Publication: 2020 Jun 12.
DOI: 10.1016/j.ejphar.2020.173243
Abstrakt: This study investigated the vasodilatory effects and acting mechanism of gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Tests were conducted in aortic rings pre-contracted with phenylephrine. Gemigliptin induced dose-dependent vasodilation of the aortic smooth muscle. Several pre-treatment groups were used to investigate the mechanism of action. While pre-treatment with paxilline, a large-conductance Ca 2+ -activated K + channel inhibitor, glibenclamide, an ATP-sensitive K + channel inhibitor, and Ba 2+ , an inwardly rectifying K + channel inhibitor, had no impact on the vasodilatory effect of gemigliptin, pre-treatment with 4-aminopyridine, a voltage-dependent K + (Kv) channel inhibitor, effectively attenuated the vasodilatory action of gemigliptin. In addition, pre-treatment with sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid significantly reduced the vasodilatory effect of gemigliptin. cAMP/PKA-related or cGMP/PKG-related signaling pathway inhibitors, including adenylyl cyclase inhibitor SQ 22536, PKA inhibitor KT 5720, guanylyl cyclase inhibitor ODQ, and PKG inhibitor KT 5823 did not alter the vasodilatory effect of gemigliptin. Similarly, elimination of the endothelium and pre-treatment with a nitric oxide (NO) synthase inhibitor (L-NAME) or small- and intermediate-conductance Ca 2+ -activated K + channels (apamin and TRAM-34, respectively) did not change the gemigliptin effect. These findings suggested that gemigliptin induces vasodilation through the activation of Kv channels and SERCA pumps independent of cAMP/PKA-related or cGMP/PKG-related signaling pathways and the endothelium. Therefore, caution is required when prescribing gemigliptin to the patients with hypotension and diabetes.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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