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Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
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2011 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 41, no 8, p. 889-897Article in journal (Refereed) Published
Abstract [en]

Background Conflicting results on exhaled NO in pulmonary hypertension (PH) exist. Therefore, we analysedexhaled NO, as well as systemic and local nitrite, a possible alternative source of NO, in PH with regard to PHaetiology.Methods Exhaled NO at multiple flow-rates, as well as plasma and salivary nitrite and nitrate, was measured in22 patients with PH and 21 healthy controls. Alveolar NO (CalvNO) and bronchial flux (J’awNO) were calculatedusing the slope–intercept model. Patients with PH were subdivided into pulmonary arterial hypertension (PAH)and PH WHO Groups II–IV, according to the WHO clinical classification of PH.Results Exhaled NO was reduced at flow-rates in the range of 20)200 mL s)1 in patients with PAH (n = 13) vs.PH WHO Group II–IV (n = 9) (P < 0Æ05 all). Patients with PAH had higher CalvNO than healthy controls [2Æ61(2Æ23, 3Æ36) vs. 1.97 ppb (1Æ22, 2Æ49), P = 0Æ03] and similar to PH WHO Group II–IV (P = 0Æ51). Patients with PAHhad lower J’awNO than patients with PH WHO Group II–IV or healthy controls [430 (371, 702) vs. 807 (557, 993)or 731 pL s)1 (580, 818), P < 0Æ05 both]. Subjects with PAH were characterized by higher levels of salivary andplasma nitrite than healthy controls (P < 0Æ05 both).Conclusions Patients with PAH have lower bronchial NO flux compared to healthy controls and patients withPH WHO Group II–IV along with elevated salivary and plasma nitrite compared to controls. This implies reducedbronchial NO synthase-derived NO formation in PAH. Increased alveolar NO levels were found in subjects withPH compared to controls, especially in subjects with PAH. This may reflect NO diffusion disturbances in thealveoli.

Place, publisher, year, edition, pages
2011. Vol. 41, no 8, p. 889-897
Keyword [en]
Exhaled nitric oxide, nitrate, nitrite, NO flow-independent exchange parameters, pulmonary hypertension
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97887DOI: 10.1111/j.1365-2362.2011.02488.xISI: 000292465600010OAI: oai:DiVA.org:uu-97887DiVA, id: diva2:172986
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2018-04-06Bibliographically approved
In thesis
1. Nitric Oxide Exchange in Central and Peripheral Airways: Determinants in Health and Respiratory Disease
Open this publication in new window or tab >>Nitric Oxide Exchange in Central and Peripheral Airways: Determinants in Health and Respiratory Disease
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Exhaled nitric oxide (NO) is a marker of eosinophilic steroid-sensitive inflammation in the airways of patients with respiratory disease. Moreover, information about the localization of inflammation in the respiratory tree is obtained by estimates of bronchial and alveolar contributions to exhaled NO.

Aims: The main aim of this thesis was to identify the determinants of exhaled NO, as well as determinants of bronchial and alveolar contributions to exhaled NO in health and disease. Smoking history, degree of IgE sensitization and effects of modulating the pharyngo-oral tract production of NO were specifically studied in this context. Other specific aims were to determine the association of exhaled NO with the presence of asthma and pulmonary hypertension (PH).

Methods: Both population-based studies and experimental studies have been performed within the frame of the thesis. The population-based studies are based on data from the European Community Respiratory Health Survey II. NO measurements at several exhalation flow rates were performed in order to estimate alveolar and bronchial contributions to exhaled NO.

Results: Both current and previous smoking were associated with decreased exhaled NO and bronchial NO flux levels. Alveolar NO concentrations were decreased in current smokers. The degree of IgE sensitization was positively related to the levels of exhaled NO and its bronchial contribution. Exhaled NO appeared to be a more specific marker of allergic inflammation than of rhinitis or asthma. Both allergic and non-allergic asthma were associated with increased exhaled NO levels, but only in never-smoking persons. The estimated alveolar NO increased after ingestion of nitrate in individuals with high nitrate turnover in the pharyngo-oral tract. Pulmonary arterial hypertension, but not other forms of PH, was associated with decreased bronchial NO flux, whereas PH of all etiologies was related to increased alveolar NO concentrations.

Conclusion: Smoking history and IgE sensitization, that are known determinants of exhaled NO, affected the bronchial and alveolar contributions to exhaled NO differently. The limitations of the simple NO pulmonary exchange models were highlighted by the paradoxical effects on estimated alveolar NO when modulating the NO production proximally, in the pharyngo-oral tract. Predominance of non-eosinophilic inflammation in ever-smoking patients with asthma could explain the poor association between the presence of asthma and exhaled NO in these patients. Different pathophysiological changes in terms of bronchial NO production and exchange were related to the etiology of pulmonary hypertension.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. p. 64
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 403
Keyword
exhaled nitric oxide, alveolar NO, bronchial NO flux, extended NO analysis, asthma, smoking, snus, IgE-sensitization, pharyngo-oral tract, nitrate, nitrite, pulmonary hypertension
Identifiers
urn:nbn:se:uu:diva-9416 (URN)978-91-554-7363-1 (ISBN)
Public defence
2008-12-19, Robergsalen, Akademiska Sjukhuset, Ingång 40, 4 tr., Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-11-27 Created: 2008-11-27Bibliographically approved
2. Pulmonary Hypertension and the Nitric Oxide System
Open this publication in new window or tab >>Pulmonary Hypertension and the Nitric Oxide System
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pulmonary hypertension (PH) is a pathophysiological state associated with several medical conditions, leading to progressive rise in pulmonary vascular resistance (PVR) and right ventricular failure. The clinical PH classification encompasses five main World Health Organization (WHO) groups; pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to lung diseases and/or hypoxia, chronic thromboembolic PH, and PH with unclear multifactorial mechanisms. Nitric oxide (NO) is a potent vasodilator. Impaired NO production via the classical L-arginine-NO synthase (NOS) pathway has been implicated in PH. Phosphodiesterase-5 (PDE5) inhibitors augment NO signalling, and are considered as one of the cornerstone treatments in PAH. The studies in this thesis aim at to explore and expand the understanding of the NO system in patients with PH.

In paper I, we found that PAH patients (WHO group 1) have lower bronchial NO flux compared to healthy controls and patients with PH (WHO group 2–4). This implies reduced bronchial NO formation in PAH. Compared to healthy controls, increased alveolar NO levels were found in patients with PH (WHO group 1-4) and patients with PAH. This may reflect NO diffusion disturbances in the alveoli. PAH patients had higher plasma and salivary levels of nitrite than healthy controls, which may reflect a compensatory upregulation of NOS-independent NO generating pathways.

In paper II, we observed that a single oral dose of vardenafil (a PDE5 inhibitor) causes rapid changes in cardiopulmonary haemodynamics in PH patients with PH (WHO group 1-4). We found a correlation between plasma vardenafil concentrations and the changes in mean pulmonary arterial pressure as well as PVR.

In paper III, we show that a single oral dose of vardenafil to patients with PH (WHO group 1-4) alter the plasma levels of arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the arginine/ADMA ratio in a favourable manner. The increase in arginine and the arginine/ADMA ratio were associated with improved cardiac index, and the increase in the arginine/ADMA ratio at 540 min correlated with the exposure to vardenafil. Higher baseline plasma levels of ADMA and SDMA and a low arginine/ADMA ratio was associated with a more severe pulmonary haemodynamic disease state in patients with PH.

In paper IV, we found that ingestion of beetroot juice, containing inorganic nitrate, increased plasma and salivary levels of nitrate and nitrite, increased exhaled NO, decreased plasma ornithine levels and increased relative arginine availability in patients with PAH compared to placebo. Higher plasma levels of nitrite after the placebo period, reflecting basal conditions, were associated with a more severe PAH phenotype. Our findings indicate that the nitrate-nitrite-NO pathway is active and upregulated in PAH patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 83
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1461
Keyword
Pulmonary hypertension, nitric oxide, ADMA, arginine, nitrate, nitrite, vardenafil, beetroot juice
National Category
Cardiac and Cardiovascular Systems
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-347767 (URN)978-91-513-0325-3 (ISBN)
Public defence
2018-06-12, Enghoffsalen, Akademiska sjukhuset, Ingång 50 bv, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2018-05-04 Created: 2018-04-06 Last updated: 2018-05-04

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Malinovschi, AndreiHenrohn, DanAlving, KjellWikström, Gerhard

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