The antidiabetic drug teneligliptin induces vasodilation via activation of PKG, Kv channels, and SERCA pumps in aortic smooth muscle.

Autor: Li H; Institute of Translational Medicine, Medical College, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases，Yangzhou University, Yangzhou, 225001, PR China., An JR; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Park M; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Choi J; 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., Kang M; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Mun SY; Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Zhuang W; Institute of Translational Medicine, Medical College, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases，Yangzhou University, Yangzhou, 225001, PR China., Seo MS; Department of Physiology, Konkuk University School of Medicine, Chungju, 27478, South Korea., Han ET; Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Han JH; Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea., Chun W; Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon, 24341, 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] 2022 Nov 15; Vol. 935, pp. 175305. Date of Electronic Publication: 2022 Sep 29.
DOI: 10.1016/j.ejphar.2022.175305
Abstrakt: Diabetes mellitus (DM) is a metabolic disease closely related to cardiovascular disease. The dipeptidyl peptidase-4 inhibitor teneligliptin is used to treat DM and has recently been shown to have a cardiovascular protective effect against diseases such as hypertension and heart failure. The present study demonstrates the vasodilatory effect of teneligliptin using aortic rings pre-contracted with phenylephrine. Teneligliptin induced a vasodilatory effect in a dose-dependent manner, with and without endothelium. In addition, pretreatment with the nitric oxide synthase inhibitor L-NAME and small-conductance Ca 2+ -activated K + channel inhibitor apamin did not alter the teneligliptin-induced vasodilatory effect. Although the adenylyl cyclase inhibitor SQ 22536 and protein kinase A (PKA) inhibitor KT 5720 did not modulate the vasodilatory effect of teneligliptin, the guanylyl cyclase inhibitor ODQ and protein kinase G (PKG) inhibitor KT 5823 effectively reduced the effect of teneligliptin. Similarly, pretreatment with the voltage-dependent K + (Kv) channel inhibitor 4-aminopyridine (4-AP) also reduced teneligliptin-induced vasodilation. However, pretreatment with the inward rectifier K + (Kir) channel inhibitor Ba 2+ , large-conductance Ca 2+ -activated K + (BK Ca ) channel inhibitor paxilline, and ATP-sensitive K + (K ATP ) channel inhibitor glibenclamide did not alter the vasodilatory effect of teneligliptin. Our data suggest that Kv7.X, but not Kv1.5 or Kv2.1, is one of the major Kv subtypes involved in teneligliptin-induced vasodilation. Furthermore, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) pump inhibitor thapsigargin and CPA inhibited the vasodilation induced by teneligliptin. Our results suggest that teneligliptin-induced vasodilation occurs via activation of PKG, SERCA pumps and Kv channels, but not the PKA signaling pathway, other K + channels, or endothelium.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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