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 [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.

Platelet activation, oxidative stress and overexpression of inducible nitric oxide synthase in moderate heart failure.

1. Chronic heart failure (CHF) is a common disabling disorder associated with thromboembolic events, the genesis of which is not yet fully understood. Nitric oxide (NO), derived from the vascular endothelium and platelets, has an important role in the physiological regulation of blood flow. It is generated from the amino acid L-arginine via NO synthase (NOS). 2. The main objective of the present study was to investigate NO production and its relationship with platelet aggregation, oxidative stress, inflammation and related amino acids in patients with moderate CHF. The expression and activity of NOS isoforms were analysed by western blotting and conversion of L-[(3)H]-arginine to L-[(3)H]-citrulline, respectively, in CHF patients (n = 12) and healthy controls (n = 15). Collagen- and ADP-induced platelet aggregation, oxidative stress (thiobarbituric acid-reactive substances (TBARS) formation and superoxide dismutase (SOD) activity) and plasma levels of amino acids and inflammatory markers (fibrinogen and C-reactive protein (CRP)) were also determined. 3. Both collagen- and ADP-induced platelet aggregation were increased in CHF patients compared with controls. Platelets from CHF patients did not show any changes in NOS activity in the presence of overexpression of inducible NOS. Systemic and intraplatelet TBARS production was elevated, whereas SOD activity was decreased in CHF patients. l-arginine plasma concentrations were lower in CHF patients than in controls. Systemic levels of CRP and fibrinogen were increased in CHF patients. 4. The results show that, in patients with moderate CHF, there is platelet activation and reduced intraplatelet NO bioavailability due to oxidative stress, which suggests a role for platelets in the prothrombotic state.