Published ahead of print on May 5, 2005, doi:10.1164/rccm.200412-1684OC
Am. J. Respir. Crit. Care Med., Volume 172, Number 3, August 2005, 352-357
A more recent version of this article appeared on August 1, 2005
Submitted on December 15, 2004
Accepted on May 3, 2005
Decreased Exhaled Nitric Oxide in Pulmonary Arterial Hypertension: Response to Bosentan Therapy
Reda E Girgis1*, Hunter C Champion2, Gregory B Diette1, Roger A Johns3, Solbert Permutt1, and J T Sylvester1
1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, United States,
2 Division Cardiology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States,
3 Department of Medicine and Anesthesiology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
* To whom correspondence should be addressed. E-mail: rgirgis{at}jhmi.edu.
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 untreated PAH patients (8 idiopathic and 2 anorexigen-associated PAH) and 12 controls.
Methods: Following a nitrite/nitrate restricted diet, NO metabolites (NOx) were assayed in 24 hr. urine collections and exhaled NO (FENO) determined at multiple expiratory flows. Analysis of the relation between FENO and flow allowed derivation of three flow-independent parameters: airway wall concentration (CW), diffusing capacity (DNO) and alveolar concentration (CA). Seven patients underwent follow-up testing after 3 months of
bosentan treatment.
Results: At baseline, FENO was markedly decreased at the two lowest expiratory flows in PAH: 21 ± 4 vs. 36 ± 4 ppb at 18 ml/s and 11 ± 2 vs. 17 ± 2 ppb at 50ml/s, for PAH and
controls, respectively (p < 0.05). CW was 33 ±11 ppb in PAH vs. 104 ±34 in controls (p = 0.04). Urinary NOx was also reduced in PAH (42 ± 6 µM NOx/mM creatinine vs. 62 ±7 in controls; p = 0.04). After bosentan, FENO, CW and urine NOx increased to control values (p < 0.05). Exclusion of the 2 anorexigen cases did not alter these results.
Conclusions: Exhaled NO at low expiratory flows was decreased in PAH due to reduced CW. Bosentan reversed these abnormalities, suggesting that suppression of NO in PAH may have been caused by endothelin.
Key words: urinary NOx, endothelin, airway
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