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.