title: Defective nitric oxide-cyclic guanosine monophosphate signaling in patients with bipolar disorder: a potential role for platelet dysfunction.
abstract: OBJECTIVE
  Bipolar disorder (BD) is associated with elevated cardiovascular mortality rates. We investigated the modulation of l-arginine-nitric oxide (NO) signaling in platelets from patients with BD at different phases.
  
  
  METHODS
  Platelets obtained from 28 patients with BD and 10 healthy volunteers were analyzed for l-arginine transport, NO synthase (NOS) activity, cyclic guanosine monophosphate content, and biomarkers of oxidative stress. Expressions of NOS isoforms, soluble guanylyl cyclase, and arginase were also measured in platelets. Amino acid and C-reactive protein levels in plasma were assessed.
  
  
  RESULTS
  Plasma concentrations of l-arginine (mean [M] ± standard error of the mean [SEM] = 97 ± 10 versus 121 ± 10 µM) and its transport into platelets (median [interquartile range] = 26.0 [28.6] versus 26.5 [43.9] pmol/10(9) cells per minute) did not differ between patients with BD and controls (p > .05). Patients with BD showed reduced NOS activity (M ± SEM = 0.037 ± 0.003 versus 0.135 ± 0.022 pmol/10(8) cells, p < .001), but not endothelial NOS, inducible NOS, and arginase expression, compared with controls (p > .05). Cyclic guanosine monophosphate content was reduced (M ± SEM = 0.022 ± 0.003 versus 0.086 ± 0.020 pmol/10(8) cells, p < .05) despite the absence of changes in soluble guanylyl cyclase expression (median [interquartile range] = 21.6 [15.5] versus 9.5 [9.4] arbitrary units, p > .05) in patients with BD. Superoxide dismutase activity, but not catalase activity, was increased in patients with BD in the manic phase (M ± SEM = 2094 ± 335 versus 172 ± 17 U/mg protein, p < .001). C-reactive protein was elevated only in manic episodes (M ± SEM = 0.8 ± 0.2 versus 0.1 ± 0.02 mg/L, p < .001).
  
  
  CONCLUSIONS
  Impaired NO generation from platelets, inflammation, and oxidative stress may play pivotal roles in the multifaceted process of cardiovascular events in BD.
authors.affiliation: Departamento de Farmacologia e Psicobiologia, Universidade do Estado do Rio de Janeiro, Brazil.
authors.forename: Paula C
authors.initials: PC
authors.lastname: Fontoura
authors.forename: Vivian Liane Mattos
authors.initials: VL
authors.lastname: Pinto
authors.forename: Cristiane
authors.initials: C
authors.lastname: Matsuura
authors.forename: Angela de C
authors.initials: Ade C
authors.lastname: Resende
authors.forename: Graziele F
authors.initials: GF
authors.lastname: de Bem
authors.forename: Marcos R
authors.initials: MR
authors.lastname: Ferraz
authors.forename: Elie
authors.initials: E
authors.lastname: Cheniaux
authors.forename: Tatiana Marlowe C
authors.initials: TM
authors.lastname: Brunini
authors.forename: Antônio Cláudio
authors.initials: AC
authors.lastname: Mendes-Ribeiro
mesh_terms: D000328:Adult; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D001714:Bipolar Disorder / Q000453:epidemiology / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000378:metabolism; D016022:Case-Control Studies; D015897:Comorbidity; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D002097:C-Reactive Protein; D001120:Arginine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D001119:Arginase; D006152:Cyclic GMP