title: Centrally acting drug moxonidine decreases reactive oxygen species via inactivation of the phosphoinositide-3 kinase signaling in the rostral ventrolateral medulla in hypertensive rats.
abstract: OBJECTIVE
  Centrally acting antihypertensive action of moxonidine is a result of activation of Imidazoline-1 receptor (I1R) in the rostral ventrolateral medulla (RVLM). Hypertension shows an increase in reactive oxygen species (ROS) in the RVLM. The present objective was to determine the phosphoinositide-3 kinase (PI3K) signaling pathway involved in the effect of moxonidine on ROS generation in the RVLM of spontaneously hypertensive rat (SHR).
  
  
  METHODS
  Wistar-Kyoto rats and SHR received intracisternal infusion (2 weeks) of tested agents which were subjected to subsequent experiments. In-situ ROS in the RVLM was evaluated by the oxidative fluorescence dye. Western blot and PCR analysis were performed to detect the expression levels of PI3K signaling pathway. Lentivirus was injected bilaterally into the RVLM for silencing PI3K signaling.
  
  
  RESULTS
  ROS production in the RVLM was dose-dependently reduced in SHRs treated with infusion of moxonidine (20 nmol/day), which was prevented by the I1R antagonist efaroxan but not by the α2-adrenoceptor antagonist yohimbine. Moxonidine pretreatment significantly blunted cardiovascular sensitivity to injection of tempol (5 nmol) or angiotensin II (10 pmol) into the RVLM in SHR. Expression levels of PI3K/Akt, nuclear factor kappa-B (NFκB), NADPHase (NOX4), and angiotensin type I receptor (AT1R) in the RVLM were markedly decreased in SHR treated with moxonidine. Infection of lentivirus containing PI3K shRNA in the RVLM effectively prevented effects of moxonidine on cardiovascular activity and expression levels of Akt, NFκB, NOX4, and AT1R.
  
  
  CONCLUSIONS
  The centrally antihypertensive drug moxonidine decreases ROS production in the RVLM through inactivation of the PI3K/Akt signaling pathway in hypertension.
authors.affiliation: aDepartment of Physiology, Second Military Medical University, Shanghai bDepartment of Physiology and Key Lab of Ministry of Education in Fertility Preservation and Maintenance, Ningxia Medical University, Yinchuan 750004, China *Yang-Kai Wang, Qiang Yu, and Xing Tan contributed equally to the writing of this article.
authors.forename: Yang-Kai
authors.initials: YK
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
authors.forename: Xing
authors.initials: X
authors.lastname: Tan
authors.forename: Zhao-Tang
authors.initials: ZT
authors.lastname: Wu
authors.forename: Ru-Wen
authors.initials: RW
authors.lastname: Zhang
authors.forename: Ya-Hong
authors.initials: YH
authors.lastname: Yang
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Yuan
authors.forename: Qi-Kuan
authors.initials: QK
authors.lastname: Hu
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Wang
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001572:Benzofurans; D004195:Disease Models, Animal; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008526:Medulla Oblongata / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D001572:Benzofurans; D007093:Imidazoles; D017382:Reactive Oxygen Species; C043482:moxonidine; D019869:Phosphatidylinositol 3-Kinases; C062597:efaroxan