Decreased exhaled nitric oxide in pulmonary arterial hypertension: Response to Bosentan therapy

Rationale: Decreased nitric oxide (NO) is considered an important pathogenetic mechanism in pulmonary arterial hypertension (PAH), but clear evidence is lacking. Objectives: We used multiple techniques to assess endogenous NO in 10 patients with untreated PAH (8 idiopathic and 2 anorexigen-associated PAH) and 12 control subjects. Methods: After a nitrite/nitrate-restricted diet, NO metabolites (NOx) were assayed in 24-hour urine collections and exhaled NO (FE_NO) determined at multiple expiratory flows. Analysis of the relation between FE_NO and flow allowed derivation of three flow-independent parameters: airway wall concentration (C_W), diffusing capacity (D_NO), and alveolar concentration (C_A). Seven patients underwent follow-up testing after 3 months of bosentan treatment. Results: At baseline, FE_NO was markedly decreased at the two lowest expiratory flows in PAH: 21 ± 4 versus 36 ± 4 ppb at 18 ml/second and 11 ± 2 versus 17 ± 2 ppb at 50 ml/second, for subjects with PAH and control subjects, respectively (p < 0.05). C_W was 33 ± 11 ppb in subjects with PAH versus 104 ± 34 in control subjects (p = 0.04). Urinary NOx was also reduced in PAH (42 ± 6 μM NOx/mM creatinine versus 62 ± 7 in control subjects; p = 0.04). After bosentan, FE_NO, C_W, and urine NOx increased to control values (p < 0.05). Exclusion of the two anorexigen cases did not alter these results. Conclusions: FE_NO at low expiratory flows was decreased in PAH due to reduced C_W. Bosentan reversed these abnormalities, suggesting that suppression of NO in PAH may have been caused by endothelin.