Antidiabetic omarigliptin dilates rabbit aorta by activating voltage‐dependent K+ channels and the sarco/endoplasmic reticulum Ca2+‐ATPase pump. (26th September 2022)

• Record Type: Journal Article
• Authors: Heo, Ryeon; Kang, Minji; Mun, Seo‐Yeong; Park, Minju; Han, Eun‐Taek; Han, Jin‐Hee; Chun, Wanjoo; Park, Hongzoo; Jung, Won‐Kyo; Choi, Il‐Whan; Park, Won Sun
• Is Part Of: Fundamental & clinical pharmacology. Volume 37:Number 1(2023)
• Page Start: 75
• Page End: 84
• Publication Date: 2022-09-26
• Subjects: aorta -- omarigliptin -- SERCA pump -- voltage‐dependent K+ channel; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/fcp.12831
• Languages: English
• ISSNs: 0767-3981

Abstract

Abstract: We investigated the vasodilatory effect of omarigliptin, an oral antidiabetic drug in the dipeptidyl peptidase‐4 inhibitor class, and its related mechanisms using phenylephrine (Phe)‐induced pre‐contracted aortic rings. Omarigliptin dilated aortic rings pre‐constricted with Phe in a dose‐dependent manner. Pretreatment with the voltage‐dependent K + channel inhibitor 4‐aminopyridine significantly attenuated the vasodilatory effect of omarigliptin, whereas pretreatment with the inwardly rectifying K + channel inhibitor Ba 2+, ATP‐sensitive K + channel inhibitor glibenclamide, and large‐conductance Ca 2+ ‐activated K + channel inhibitor paxilline did not alter its vasodilation. Pretreatment with the sarco/endoplasmic reticulum Ca 2+ ‐ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid significantly reduced the vasodilatory effect of omarigliptin. Neither cAMP/PKA‐related signaling pathway inhibitors nor cGMP/PKG‐related signaling pathway inhibitors modulated the vasodilatory effect of omarigliptin. Removal of endothelium did not diminish the vasodilatory effect of omarigliptin. Furthermore, pretreatment with the nitric oxide synthase inhibitor L‐NAME or small‐conductance Ca 2+ ‐activated K + channel inhibitor apamin, together with the intermediate‐conductance Ca 2+ ‐activated K + channel inhibitor TRAM‐34, did not influence the vasodilatory effect of omarigliptin. In conclusion, omarigliptin induced vasodilation in rabbit aortic smooth muscle by activating voltage‐dependent K + channels and the SERCA pump independently of other K + channels, cAMP/PKA‐ and cGMP/PKG‐related signaling pathways, and the endothelium.