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  • Title: Antidiabetic omarigliptin dilates rabbit aorta by activating voltage-dependent K+ channels and the sarco/endoplasmic reticulum Ca2+ -ATPase pump.
    Author: Heo R, Kang M, Mun SY, Park M, Han ET, Han JH, Chun W, Park H, Jung WK, Choi IW, Park WS.
    Journal: Fundam Clin Pharmacol; 2023 Feb; 37(1):75-84. PubMed ID: 36093990.
    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 Ba2+ , ATP-sensitive K+ channel inhibitor glibenclamide, and large-conductance Ca2+ -activated K+ channel inhibitor paxilline did not alter its vasodilation. Pretreatment with the sarco/endoplasmic reticulum Ca2+ -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 Ca2+ -activated K+ channel inhibitor apamin, together with the intermediate-conductance Ca2+ -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.
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