Abstract:
This study investigated the vasodilatory effects and acting mechanism of gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Tests were conducted in aortic rings pre-contracted with phenylephrine. Gemigliptin induced dose-dependent vasodilation of the aortic smooth muscle. Several pre-treatment groups were used to investigate the mechanism of action. While pre-treatment with paxilline, a large-conductance Ca2+-activated K+ channel inhibitor, glibenclamide, an ATP-sensitive K+ channel inhibitor, and Ba2+, an inwardly rectifying K+ channel inhibitor, had no impact on the vasodilatory effect of gemigliptin, pre-treatment with 4-aminopyridine, a voltage-dependent K+ (Kv) channel inhibitor, effectively attenuated the vasodilatory action of gemigliptin. In addition, pre-treatment with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid significantly reduced the vasodilatory effect of gemigliptin. cAMP/PKA-related or cGMP/PKG-related signaling pathway inhibitors, including adenylyl cyclase inhibitor SQ 22536, PKA inhibitor KT 5720, guanylyl cyclase inhibitor ODQ, and PKG inhibitor KT 5823 did not alter the vasodilatory effect of gemigliptin. Similarly, elimination of the endothelium and pre-treatment with a nitric oxide (NO) synthase inhibitor (L-NAME) or small- and intermediate-conductance Ca2+-activated K+ channels (apamin and TRAM-34, respectively) did not change the gemigliptin effect. These findings suggested that gemigliptin induces vasodilation through the activation of Kv channels and SERCA pumps independent of cAMP/PKA-related or cGMP/PKG-related signaling pathways and the endothelium. Therefore, caution is required when prescribing gemigliptin to the patients with hypotension and diabetes.