Defective Nitric Oxide Cyclic Guanosine Monophosphate Signaling in Patients With Bipolar Disorder: A Potential Role for Platelet Dysfunction

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 [SEMI = 97 +/- 10 versus 121 +/- 10 mu M) 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. Key words: nitric oxide, bipolar disorder, platelet, oxidative stress.