The antidiabetic drug teneligliptin induces vasodilation via activation of PKG, Kv channels, and SERCA pumps in aortic smooth muscle

Abstract

Diabetes mellitus (DM) is a metabolic disease closely related to cardiovascular disease. The dipeptidyl peptidase-4 inhibitor teneligliptin is used to treat DM and has recently been shown to have a cardiovascular protective effect against diseases such as hypertension and heart failure. The present study demonstrates the vasodilatory effect of teneligliptin using aortic rings pre-contracted with phenylephrine. Teneligliptin induced a vasodilatory effect in a dose-dependent manner, with and without endothelium. In addition, pretreatment with the nitric oxide synthase inhibitor L-NAME and small-conductance Ca2+-activated K+ channel inhibitor apamin did not alter the teneligliptin-induced vasodilatory effect. Although the adenylyl cyclase inhibitor SQ 22536 and protein kinase A (PKA) inhibitor KT 5720 did not modulate the vasodilatory effect of teneligliptin, the guanylyl cyclase inhibitor ODQ and protein kinase G (PKG) inhibitor KT 5823 effectively reduced the effect of teneligliptin. Similarly, pretreatment with the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine (4-AP) also reduced teneligliptin-induced vasodilation. However, pretreatment with the inward rectifier K+ (Kir) channel inhibitor Ba2+, large-conductance Ca2+-activated K+ (BKCa) channel inhibitor paxilline, and ATP-sensitive K+ (KATP) channel inhibitor glibenclamide did not alter the vasodilatory effect of teneligliptin. Our data suggest that Kv7.X, but not Kv1.5 or Kv2.1, is one of the major Kv subtypes involved in teneligliptin-induced vasodilation. Furthermore, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor thapsigargin and CPA inhibited the vasodilation induced by teneligliptin. Our results suggest that teneligliptin-induced vasodilation occurs via activation of PKG, SERCA pumps and Kv channels, but not the PKA signaling pathway, other K+ channels, or endothelium.