Exhaled Nitric Oxide During Exercise in Primary Pulmonary Hypertension and Pulmonary Fibrosis

doi:10.1378/chest.111.1.44

Chest

Volume 111, Issue 1, January 1997, Pages 44-50

https://doi.org/10.1378/chest.111.1.44 Get rights and content

Study objectives

Nitric oxide (NO), a potent vasodilator, is present in the exhaled air of humans. We wished to quantify NO production in patients with abnormalities of the pulmonary circulation. Participants: Nine patients with primary pulmonary hypertension (PPH), six with pulmonary fibrosis (PF), and 20 normal volunteers were studied.

Interventions

All subjects were studied at rest and during continuous incremental (ramp) cycle ergometry exercise. All patients with PPH and nine matched normal volunteers also performed constant exercise at equal absolute work rates.

Measurements and results

The concentration of NO was measured continuously in mixed expired air, and the rate of NO production ( $\dot{V}$ NO) calculated. Peak exercise capacity was markedly impaired in both patient groups. VNO was similar at rest in the PPH patients (142±84 nL/min) and the normal subjects (117±45 nL/min), but lower in the PF patients (66±13 nL/min; p<0.05; analysis of variance with Bonferonni correction). While VNO in normal subjects more than doubled by peak exercise to 268±85 nL/min, there was no significant rise with exercise in either patient group (PPH, 155±81 nL/min; PF, 91±67 nL/min). Constant work rate exercise induced a significant rise in VNO in the normal subjects (rest, 101±68 nL/min; exercise, 147±87 nL/min; p<0.001) but no significant change in the PPH patients (rest, 127±111 nL/min; exercise, 68±65 nL/min).

Conclusions

We conclude that the low resting VNO in PF may be due to loss of normal functional pulmonary capillary bed. The increase in VNO seen in normal subjects may be associated with dilatation and recruitment of the pulmonary capillary bed during exercise, and failure to increase VNO during exercise in disease states may reflect an inability to recruit the capillary bed.

Section snippets

Subjects

Nine patients with clinically stable PPH were studied. The mean duration of disease was 28.1 months (range, 5.4 to 92.7 months). Seven patients were being treated with continuous IV infusions of prostacyclin (epoprostenol sodium [Flolan]; Wellcome) at a mean dose of 8.7 ng/kg/min (range, 3 to 20) and five were being treated with diuretics. Four patients were taking calcium channel antagonists and five were taking digoxin. None was taking antibiotics. All had tricuspid regurgitation, and peak

RESULTS

All subjects completed the exercise tests uneventfully. Peak exercise work rate and maximal $\dot{V}$ o₂ ( $\dot{V}$ o₂max) were similar in both patient groups but much greater in the normal subjects, indicating marked impairment of exercise capacity in both PPH and PF patients (Table 2). Representative examples of the change with incremental exercise in mixed exhaled NO concentration and VNO are shown in Figures 2 and 3, respectively. Mixed exhaled NO concentration was greater at rest than at peak

DISCUSSION

To our knowledge, this is the first study in which NO production has been determined continuously during rest and exercise, and it confirms that NO is present in the exhaled breath of normal subjects and patients with PPH and PF. In addition, we have shown reduced levels of VNO at rest in patients with PF, and an abnormal response to exercise in both PPH and PF patients. VNO increased progressively with incremental exercise in normal subjects, but did not increase in either patient group

ACKNOWLEDGMENT

We are extremely grateful to Joy Beckman, RN, for her invaluable help with recruitment and care of the patients with PPH, and to L. Wilkinson for construction of the NO signal amplifier.

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Biomarkers in Pulmonary Vascular Disease: Gauging Response to Therapy
2017, American Journal of Cardiology
Citation Excerpt :
This acute overproduction of NO can result in increases in exhaled NO due to extravascular production of NO. Measurement of changes in the fractional NO concentration in expired breath (FENO) aids in evaluating and predicting an asthma patient's response to anti-inflammatory therapy, as an adjunct to established clinical and laboratory assessments of asthma. However, baseline levels of exhaled NO have been shown to be significantly lower in patients with PAH than in controls,29,30 although this did not hold true in all studies.24,31,32 One would expect lower vascular endothelial NO production in patients with PAH, and the inability to generate NO leads to impaired vasodilation and therefore elevated chronic tone on vessels and development of PAH with remodeling.
Biomarkers are increasingly being investigated in the treatment of pulmonary vascular disease. In particular, the signaling pathways targeted by therapies for pulmonary arterial hypertension provide biomarkers that potentially can be used to guide therapy and to assess clinical response as an alternative to invasive procedures such as right-sided cardiac catheterization. Moreover, the growing use of combination therapy for both the initial and subsequent treatment of pulmonary arterial hypertension highlights the need for biomarkers in this treatment approach. Currently approved therapies for pulmonary arterial hypertension target 3 major signaling pathways: the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, the endothelin pathway, and the prostacyclin pathway. Although the main biomarker used in practice and evaluated in clinical trials is N-terminal pro-brain natriuretic peptide, other putative biomarkers include the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine, NO metabolites including S-nitrosothiols and nitrite, exhaled NO, endothelins, cyclic guanosine monophosphate, cyclic adenosine monophosphate, and atrial natriuretic peptide. This review describes accessible biomarkers, related to the actual molecules targeted by current therapies, for measuring and predicting response to the individual pulmonary arterial hypertension treatment classes as well as combination therapy.
Riociguat: A novel therapeutic option for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
2014, Canadian Journal of Cardiology
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious and often fatal diseases. The pathophysiology of both diseases is complex and in part is attributed to alterations in the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate pathway. Riociguat, a novel sGC stimulator, acts on this pathway through a dual mechanism of action by directly stimulating sGC in a NO-independent manner and also increasing the sensitivity of sGC to NO. Based on benefits from clinical trials for both PAH and CTEPH, riociguat was approved by Health Canada and the US Food and Drug Administration as the first medical therapy for patients with CTEPH who are deemed inoperable or have residual/recurrent PH after pulmonary endarterectomy (PEA), and as a novel treatment option for patients with PAH. This article reviews the key findings from the phase III trials for riociguat that led to these approvals and the implications this has for the treatment of patients with PAH and CTEPH.
L’hypertension artérielle pulmonaire (HAP) et l’hypertension pulmonaire thromboembolique chronique (HPTEC) sont des maladies sérieuses et souvent fatales. La physiopathologie de ces deux maladies est complexe et est en partie attribuée aux modifications des voies de l’oxyde nitrique (NO), de la guanylyl cyclase soluble (sGC) et de la guanosine monophosphate cyclique. Le riociguat, un nouveau stimulateur de la sGC, agit sur cette voie par un double mécanisme d’action en stimulant directement la sGC indépendamment du NO et en augmentant également la sensibilité de la sGC au NO. En se basant sur les avantages établis par les essais cliniques portant sur l’HAP et l’HPTEC, Santé Canada et la Food and Drug Administration des États-Unis ont approuvé le riociguat comme étant le premier traitement médical à offrir aux patients souffrant d’HPTEC qui sont considérés inopérables ou ont une HP résiduelle ou récurrente après l’endartériectomie pulmonaire (AEP) et comme nouvelle option de traitement des patients souffrant d’une HAP. Cet article passe en revue les principales conclusions des essais de phase III portant sur le riociguat qui ont mené à ces autorisations de mise sur le marché, et sur ses conséquences sur le traitement des patients souffrant d’une HAP et d’une HPTEC.
Short-term effects of electronic and tobacco cigarettes on exhaled nitric oxide
2014, Toxicology and Applied Pharmacology
The objective of this study was to compare the short-term respiratory effects due to the inhalation of electronic and conventional tobacco cigarette-generated mainstream aerosols through the measurement of the exhaled nitric oxide (eNO). To this purpose, twenty-five smokers were asked to smoke a conventional cigarette and to vape an electronic cigarette (with and without nicotine), and an electronic cigarette without liquid (control session).
Electronic and tobacco cigarette mainstream aerosols were characterized in terms of total particle number concentrations and size distributions. On the basis of the measured total particle number concentrations and size distributions, the average particle doses deposited in alveolar and tracheobronchial regions of the lungs for a single 2-s puff were also estimated considering a subject performing resting (sitting) activity.
Total particle number concentrations in the mainstream resulted equal to 3.5 ± 0.4 × 10⁹, 5.1 ± 0.1 × 10⁹, and 3.1 ± 0.6 × 10⁹ part. cm^− 3 for electronic cigarettes without nicotine, with nicotine, and for conventional cigarettes, respectively. The corresponding alveolar doses for a resting subject were estimated equal to 3.8 × 10¹⁰, 5.2 × 10¹⁰ and 2.3 × 10¹⁰ particles.
The mean eNO variations measured after each smoking/vaping session were equal to 3.2 ppb, 2.7 ppb and 2.8 ppb for electronic cigarettes without nicotine, with nicotine, and for conventional cigarettes, respectively; whereas, negligible eNO changes were measured in the control session. Statistical tests performed on eNO data showed statistically significant differences between smoking/vaping sessions and the control session, thus confirming a similar effect on human airways whatever the cigarette smoked/vaped, the nicotine content, and the particle dose received.
The potential of biomarkers in pulmonary arterial hypertension
2012, American Journal of Cardiology
Citation Excerpt :
Further evidence of the role of eNOS in PAH is that increased plasma levels of dimethylarginines (DMAs), which have been shown to adversely affect endogenous NO levels either by inhibiting NO production (asymmetric DMA) or by arginine uptake (symmetric DMA),16 are related to unfavorable hemodynamics and increased mortality in idiopathic PAH.17 Because pulmonary NO production cannot be assessed from standard serum samples, local underproduction of NO has been quantified in exhaled airway gases,18,19 and an increase in exhaled NO has been related to response to PAH treatment in small studies.20–22 These findings remain to be confirmed in a larger cohort of patients with PAH.
Effective management of patients with pulmonary arterial hypertension (PAH) requires comprehensive prognostic evaluation in order to determine optimal management strategies. Although a number of clinical and hemodynamic parameters linked to PAH prognosis have been identified, some are associated with significant limitations (eg, invasive techniques, subjective measures). There is a need for noninvasive and objective measures to be established that function as biomarkers for the diagnosis and assessment of disease prognosis, and that determine response to therapy in patients with PAH. Reflecting the highly complex etiology of the disease, a large number of potential biomarkers have been, and continue to be, investigated in PAH, including those reflecting right heart function, endothelial dysfunction, and markers of inflammation and second organ failure. However, it has become clear that scientifically interesting biomarkers may not necessarily be clinically useful. Of the range of biomarkers investigated in PAH to date, only brain natriuretic peptide and its N-terminal cleavage product have been included as prognostic parameters in treatment guidelines. It is unlikely that any single biomarker will provide all the relevant information required for an individual patient, and the potential for combining markers is currently of considerable interest. Future studies are required to determine the optimal combination of existing and emerging biomarkers in the clinical setting.
Continuous haemodynamic monitoring during exercise in patients with pulmonary hypertension
2005, International Journal of Cardiology
Right heart haemodynamic parameters can be recorded continuously with the help of an implanted haemodynamic monitor. Aim of the study was to assess the haemodynamic response with and without inhalation of iloprost during cardiopulmonary exercise testing (CPET) in patients with pulmonary hypertension.
Five female patients with documented pulmonary hypertension (mean±S.D. age 47±16 years, 4 arterial, 1 venous) previously implanted with a haemodynamic monitor underwent an incremental exercise test on 2 separate days. The tests were performed before and immediately after inhalation of a single dose of iloprost (17 μg). Parameters recorded by the device were right ventricular (RV)-afterload (RV systolic pressure, RVSP), RV-preload (RV diastolic pressure, RVDP), estimated pulmonary artery diastolic pressure (ePAD), heart rate (HR) and maximum positive rate of RV pressure development (RVdP/dt) (reflecting the dynamic and inotropic state of the RV).
After inhalation of iloprost, RV systolic pressure was always reduced at rest. It was followed by an increase with higher workloads without any difference at VO_2peak. The time course of RV systolic pressure was not linear with a flattening at higher workload during the test. This behaviour was found irrespective of iloprost treatment. The remaining determinants of RV performance showed no relevant differences and a linear behaviour during the exercise test.
Inhalation of aerosolised iloprost resulted in a reduction in right ventricular pressure at rest but not at maximal workload. The implantable haemodynamic monitor (IHM) may be useful for the evaluation of RV haemodynamics during exercise and in assessing treatment efficacy.
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: Supported by the Medical Graphics Corporation, St. Paul, Minn, and by the St. John's Cardiovascular Research Center, Torrance, Calif (Dr. Riley).

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Chest

Clinical Investigations: Pulmonary VasculatureExhaled Nitric Oxide During Exercise in Primary Pulmonary Hypertension and Pulmonary Fibrosis

Study objectives

Interventions

Measurements and results

Conclusions

Section snippets

Subjects

RESULTS

DISCUSSION

ACKNOWLEDGMENT

Lancet

Lancet

Biochem Biophys Res Commun

Lancet

Lancet

Respir Physiol

Chest

Eur J Pharmacol

Primarily nasal origin of exhaled nitric oxide and absence in Kartagener's syndrome

Eur Respir J

High nitric oxide production in human paranasal sinuses

Nature Med

Exhaled nitric oxide in isolated pig lungs

J Appl Physiol

Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension

N Engl J Med

Oxygen uptake kinetics in response to exercise in patients with pulmonary vascular disease

Am Rev Respir Dis

Principles of exercise testing and interpretation

Breath-by-breath measurement of true alveolar gas exchange

J Appl Physiol

Clinical Investigations: Pulmonary Vasculature
Exhaled Nitric Oxide During Exercise in Primary Pulmonary Hypertension and Pulmonary Fibrosis