The anti-diabetic drug trelagliptin induces vasodilation via activation of Kv channels and SERCA pumps

Aims: In this study, we investigated the vasodilatory effects of trelagliptin (a dipeptidyl peptidase-4 inhibitor) and its related mechanisms using rabbit aortic rings.

Main methods: Arterial tone measurement was performed in rabbit thoracic aortic rings.

Key findings: Trelagliptin induced vasodilation in a dose-dependent manner. Pretreatment with the ATP-sensitive K⁺ channel inhibitor glibenclamide, large-conductance Ca²⁺-activated K⁺ channel inhibitor paxilline, and inwardly rectifying K⁺ channel inhibitor Ba²⁺ did not affect the vasodilatory effect of trelagliptin. However, pretreatment with the voltage-dependent K⁺ (Kv) channel inhibitors 4-aminopyridine and tetraethylammonium significantly attenuated the vasodilatory effect of trelagliptin, suggesting that the vasodilatory effect of trelagliptin is associated with Kv channel activation. Although pretreatment with Kv1.5 and Kv2.1 subtype inhibitors did not affect the response to trelagliptin, pretreatment with a Kv7.X subtype inhibitor effectively reduced the vasodilatory effect of trelagliptin. Furthermore, sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump inhibitors also significantly attenuated the vasodilatory effect of trelagliptin. These effects, however, were not affected by pretreatment with Ca²⁺ channel inhibitors, adenylyl cyclase/PKA inhibitors, guanylyl cyclase/PKG inhibitors, or removal of the endothelium.

Significance: From these results, we concluded that the vasodilatory effect of trelagliptin was associated with the activation of Kv channels (primary the Kv7.X subtype) and SERCA pump regardless of other K⁺ channels, Ca²⁺ channels, cAMP/PKA-related or cGMP/PKG-related signaling pathways, and the endothelium. Therefore, caution is required when prescribing trelagliptin to the patients with hypotension and diabetes.