The anti-diabetic drug alogliptin induces vasorelaxation via activation of Kv channels and SERCA pumps.

Autor: Jung HS; Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Seo MS; Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., An JR; Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Heo R; Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Kang M; Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Han ET; Institute of Medical Sciences, Department of Medical Environmental Biology and Tropical 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., Song G; Department of Urology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Son YK; Biological and Genetic Resources Assessment Division, National Institute of Biological Resources, Incheon, 22689, South Korea., Jung WK; Department of Biomedical Engineering, Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, 48513, South Korea., Choi IW; Department of Microbiology, College of Medicine, Inje University, Busan, 48516, South Korea., Na SH; Institute of Medical Sciences, Department of Obstetrics and Gynecology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea. Electronic address: lahun@kangwon.ac.kr., Park WS; Institute of Medical Sciences, 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] 2021 May 05; Vol. 898, pp. 173991. Date of Electronic Publication: 2021 Mar 05.
DOI: 10.1016/j.ejphar.2021.173991
Abstrakt: In the present study, we investigated the vasorelaxant effects of alogliptin, an oral antidiabetic drug in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, using phenylephrine (Phe)-induced pre-contracted aortic rings. Alogliptin induced vasorelaxation in a dose-dependent manner. Pre-treatment with the voltage-dependent K + (Kv) channel inhibitor 4-aminopyridine (4-AP) significantly decreased the vasorelaxant effect of alogliptin, whereas pre-treatment with the inwardly rectifying K + (Kir) channel inhibitor Ba 2+ , ATP-sensitive K + (K ATP ) channel inhibitor glibenclamide, and large-conductance Ca 2+ -activated K + (BK Ca ) channel inhibitor paxilline did not alter the effects of alogliptin. Although pre-treatment with the Ca 2+ channel inhibitor nifedipine did not affect the vasorelaxant effect of alogliptin, pre-treatment with the sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid effectively attenuated the vasorelaxant response of alogliptin. Neither cGMP/protein kinase G (PKG)-related signaling pathway inhibitors (guanylyl cyclase inhibitor ODQ and PKG inhibitor KT 5823) nor cAMP/protein kinase A (PKA)-related signaling pathway inhibitors (adenylyl cyclase inhibitor SQ 22536 and PKA inhibitor KT 5720) reduced the vasorelaxant effect of alogliptin. Similarly, the vasorelaxant effect of alogliptin was not changed by endothelium removal or pre-treatment with the nitric oxide (NO) synthase inhibitor L-NAME or the small- and intermediate-conductance Ca 2+ -activated K + (SK Ca and IK Ca ) channel inhibitors apamin and TRAM-34. Based on these results, we suggest that alogliptin induced vasorelaxation in rabbit aortic smooth muscle by activating Kv channels and the SERCA pump independent of other K + channels, cGMP/PKG-related or cAMP/PKA-related signaling pathways, and the endothelium.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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