title: Aliskiren improves endothelium-dependent relaxation of thoracic aorta by activating PI3K/Akt/eNOS signal pathway in SHR.
abstract: Aliskiren, a direct renin blocker, has been approved for the treatment of hypertension. However, the potential role of aliskiren on vascular endothelial function in spontaneously hypertensive rats (SHR) remains unclear. In the present study, male SHRs at 12 weeks of age were orally administrated 30 mg/kg per day or 60 mg/kg per day aliskiren. After a 4-week treatment, aliskiren showed a significant effect on the reduction of blood pressure at a dosage of 60 mg/kg per day, but not of 30 mg/kg per day. Moreover, both dosages of aliskiren improved endothelium-dependent relaxation, reduced dihydroethidium fluorescence intensity, decreased level of malondialdehyde but heightened total antioxidant capacity and superoxide dismutase activity in thoracic aorta in SHR. Aliskiren also markedly increased expression of p85α, an important subunit of phosphatidylinositol 3 kinase (PI3K), enhancing phosphorylation of protein kinase B (Akt) at Ser473 and endothelial nitric oxide synthase (eNOS) at Ser1177, as well as cyclic guanosine-3'5'-monophosphate (cGMP, a sensitive index of biological activity of nitric oxide) concentration. Furthermore, both anti-oxidative and endothelium protective effects of aliskiren were diminished when PI3K was inhibited in vivo. The data presented here indicates that, aliskiren improves endothelium-dependent relaxation of thoracic aorta in SHR, predominantly through attenuating oxidative stress and activation of the PI3K/Akt/eNOS pathway. These data might propose novel strategies to prevent and improve vascular endothelial dysfunction.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Xie
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.|Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Meng
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005650:Fumarates / Q000494:pharmacology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D015398:Signal Transduction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000109:Acetylcholine; D000577:Amides; D004791:Enzyme Inhibitors; D005650:Fumarates; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C446481:aliskiren
keywords: endothelial function; endothelial nitric oxide synthase; hypertension; oxidative injury; renin angiotensin system inhibitors