Antidiabetic omarigliptin dilates rabbit aorta by activating voltage-dependent K⁺ channels and the sarco/endoplasmic reticulum Ca²⁺ -ATPase pump

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.