Dipeptidyl peptidase-4 inhibitor sitagliptin induces vasorelaxation via the activation of Kv channels and PKA

Abstract

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 concentration-dependent manner but the inhibition of voltage-dependent K+ (Kv) channels by pretreatment with 4-aminopyridine (4-AP) effectively reduced this effect. By contrast, the inhibition of inward rectifier K+ (Kir) channels by pretreatment with barium (Ba2+), large-conductance calcium (Ca2+)-activated K+ (BKCa) channels with paxilline, and adenosine triphosphate (ATP)-sensitive K+ (KATP) channels with glibenclamide did not change this effect. Although the application of SQ 22536, which is an adenylyl cyclase inhibitor, also did not change this effect, treatment with KT 5720, a protein kinase A (PKA) inhibitor, effectively reduced the vasorelaxant effects of sitagliptin. ODQ, which is a guanylyl cyclase inhibitor, and KT 5823, a protein kinase G (PKG) inhibitor, did not impact the effect. Furthermore, neither the inhibition of Ca2+ channels by pretreatment with nifedipine nor the inhibition of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps by pretreatment with thapsigargin changed 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), or by inhibition of small- and intermediate-conductance Ca2+-activated K+ channels (SKCa and IKCa) using apamin and TRAM-34. Taken together, these results suggest that sitagliptin induces vasorelaxation by inhibiting both membrane potential (Em)-dependent and -independent vasoconstriction and activating PKA and Kv channels independently of PKG signaling pathways, other K+ channels, SERCA pumps, and the endothelium.