title: Angiotensin II inhibits neuronal nitric oxide synthase activation through the ERK1/2-RSK signaling pathway to modulate central control of blood pressure.
abstract: BACKGROUND
  Angiotensin (Ang) II exerts diverse physiological actions in both the peripheral and central neural systems. It was reported that the activity of Ang II is higher in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHRs) and that angiotensin type-1 receptors are colocalized with NAD(P)H oxidase in the neurons of the NTS, resulting in the induction of local reactive oxygen species production by Ang II. However, the signaling mechanisms of Ang II that induce hypertension remain unclear.
  
  
  OBJECTIVE
  The aim of this study was to investigate the possible signaling pathways involved in Ang II-mediated blood pressure regulation in the NTS.
  
  
  RESULTS
  Male SHRs were treated with losartan or tempol for 2 weeks, after which systolic blood pressure was observed to decrease significantly. Dihydroethidium staining showed many cells with high reactive oxygen species in the NTS of SHRs. The addition of losartan or tempol decreased the numbers of reactive oxygen species-positive cells in the NTS. The systemic administration of losartan or tempol reduced the systolic blood pressure and increased NO production. Immunoblotting and immunohistochemical analysis further showed that inhibition of Ang II activity by losartan or tempol significantly increased the expression extracellular signal-regulated kinase (ERK)1/2, ribosomal protein S6 kinase (RSK), and also increased neuronal NO synthase (nNOS) phosphorylation. RSK was also found to bind directly to nNOS and induce phosphorylation at the Ser1416 position.
  
  
  CONCLUSIONS
  Taken together, these results suggest that the ERK1/2-RSK-nNOS signaling pathway may play a significant role in Ang II-mediated central blood pressure regulation.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Rd., Kaohsiung, Taiwan 813, Republic of China.
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Cheng
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Ho
authors.forename: Che-Se
authors.initials: CS
authors.lastname: Tung
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Cheng
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Ching-Jiunn
authors.initials: CJ
authors.lastname: Tseng
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D018384:Oxidative Stress; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017382:Reactive Oxygen Species / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D017552:Solitary Nucleus / Q000187:drug effects / Q000201:enzymology*; D013113:Spin Labels; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D013113:Spin Labels; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019808:Losartan; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C001803:tempol