Page 10 - Y. Vascular biology

[Y. Vascular biology-6]

Antidiabetic drug sitagliptin induces vasorelaxation via the

activation of PKA and voltage-gated K+ channels

Mi Seon Seo¹, Won Sun Park¹

¹Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea

The present study investigated the vasorelaxant effects of sitagliptin, which is a dipeptidyl peptidase-4 (DPP-4)
inhibitor in aortic rings pre-contracted with phenylephrine (Phe). Sitagliptin induced vasorelaxation in a dose-
dependent manner but the inhibition of voltage-gated K+ (Kv) channels by pretreatment with 4-aminopyridine (4-

AP) effectively reduced the vasorelaxant effect of sitagliptin. Although the application of SQ 22536, which is an

adenylyl cyclase inhibitor, also did not change this effect, treatment with KT 5720, a PKA inhibitor, effectively reduced
the vasorelaxant effects of sitagliptin. ODQ, which is a guanylyl cyclase inhibitor, and KT 5823, a PKG inhibitor, did
not impact the effect. Similarly, the effects of sitagliptin were not altered by eliminating the endothelium, by

pretreatment with a nitric oxide (NO) synthase inhibitor (L-NAME). Furthermore, neither the inhibition of Ca2+
channels by pretreatment with nifedipine nor the inhibition of SERCA pumps by pretreatment with thapsigargin

changed the effect. Taken together, these results suggest that sitagliptin induces vasorelaxation by activating PKA
and Kv channels independent of PKG signaling pathways, other K+ channels, Ca2+ channels, SERCA pumps, and

the endothelium.