We investigated whether
sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuates arrhythmias through inhibiting
nerve growth factor (
NGF) expression in post-infarcted normoglycemic rats, focusing on
adenosine and
reactive oxygen species production. DPP-4 bound
adenosine deaminase has been shown to catalyse extracellular
adenosine to
inosine.
DPP-4 inhibitors increased
adenosine levels by inhibiting the complex formation. Normoglycemic male Wistar rats were subjected to coronary
ligation and then randomized to either saline or
sitagliptin in in vivo and ex vivo studies. Post-
infarction was associated with increased oxidative stress, as measured by myocardial
superoxide,
nitrotyrosine and
dihydroethidium fluorescent staining. Measurement of myocardial
norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with
sham. Compared with vehicle, infarcted rats treated with
sitagliptin significantly increased interstitial
adenosine levels and attenuated oxidative stress. Sympathetic hyperinnervation was blunted after administering
sitagliptin, as assessed by immunofluorescent analysis and western blotting and real-time quantitative RT-PCR of
NGF. Arrhythmic scores in the
sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Ex vivo studies showed a similar effect of erythro-9-(2-hydroxy-3-nonyl)
adenine (an
adenosine deaminase inhibitor) to
sitagliptin on attenuated levels of
superoxide and
NGF. Furthermore, the beneficial effects of
sitagliptin on
superoxide anion production and
NGF levels can be reversed by 8-cyclopentyl-1,3-dipropulxanthine (
adenosine A1 receptor antagonist) and exogenous
hypoxanthine.
Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation via
adenosine A1 receptor and
xanthine oxidase-dependent pathways, which converge through the attenuated formation of
superoxide in the non-diabetic infarcted rats.