title: Angiotensin II/AT2 receptor-induced vasodilation in stroke-prone spontaneously hypertensive rats involves nitric oxide and cGMP-dependent protein kinase.
abstract: BACKGROUND
  Angiotensin II (Ang II) induces vasodilation, in part, through angiotensin type 2 receptor (AT2R)-induced actions in conditions associated with angiotensin type 1 receptor (AT1R) blockade and AT2R upregulation. Ang II/AT2R-induced vasodilation involves nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-dependent processes. We previously demonstrated that AT2R-mediated effects involve inhibition of the RhoA/Rho kinase pathway. However, molecular mechanisms underlying this phenomenon are unknown.
  
  
  OBJECTIVE
  In the present in-vivo study we tested the hypothesis that AT2R-elicited vasodilation is associated with nitric oxide synthase (NOS) activation and NO production, and that a cGMP-dependent protein kinase (cGKI), which inactivates RhoA, is upregulated when stroke-prone spontaneously hypertensive rats (SHRSP) are treated with AT1R blockers.
  
  
  METHODS
  SHRSP and Wistar-Kyoto (WKY) rats were treated with the AT1R blocker valsartan for 14 days. Dilatory responses to Ang II with or without the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) were performed in norepinephrine-precontracted vessels in the presence of valsartan. Expression of AT2R, endothelial NOS (eNOS) and cGKI was assessed by immunoblotting. NO bioavailability and NAD(P)H oxidase activity were evaluated by chemiluminescence.
  
  
  RESULTS
  Ang II elicited vasodilation in valsartan-treated SHRSP. L-NAME inhibited this effect, indicating a role for NO. eNOS expression and NO concentration were increased twofold by valsartan, only in SHRSP. Expression of cGKI was reduced in SHRSP and restored after valsartan treatment. NAD(P)H oxidase activity was approximately threefold higher in SHRSP versus WKY (P < 0.05) and reduced by valsartan.
  
  
  CONCLUSIONS
  Ang II, via AT2R, facilitates vasodilation through NOS/NO-mediated pathways and upregulation [corrected] of CGK1 [corrected] after chronic AT1R antagonism. These effects may contribute in part to beneficial actions of AT1R blockers in the treatment of hypertension.
authors.affiliation: Lady Davis Institute for Medical Research, SMBD Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Carmine
authors.initials: C
authors.lastname: Savoia
authors.forename: Talin
authors.initials: T
authors.lastname: Ebrahimian
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Gratton
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D011945:Receptors, Angiotensin / Q000502:physiology*; D020521:Stroke / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D009569:Nitric Oxide; D000068756:Valsartan; D017869:Cyclic GMP-Dependent Protein Kinases; D014633:Valine