Sitagliptin attenuates sympathetic innervation via modulating reactive oxygen species and interstitial adenosine in infarcted rat hearts |
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| Authors: | Tsung‐Ming Lee Wei‐Ting Chen Chen‐Chia Yang Shinn‐Zong Lin Nen‐Chung Chang |
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| Affiliation: | 1. Department of Medicine, Cardiology Section, China Medical University‐An Nan Hospital, Tainan, Taiwan;2. Department of Medicine, China Medical University, Taichung, Taiwan;3. Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan;4. Neuropsychiatry Center, China Medical University Hospital, Taichung, Taiwan;5. Graduate Institute of Immunology, China Medical University, Taichung, Taiwan;6. Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan;7. Department of Neurosurgery, China Medical University‐An Nan Hospital, Tainan, Taiwan;8. Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan |
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| Abstract: | 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. |
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| Keywords: | adenosine arrhythmia nerve growth factor myocardial infarction reactive oxygen species |
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