Decreased Whole Body Endogenous Nitric Oxide Production in Patients with Primary Pulmonary Hypertension

Demoncheaux, Eric; Higenbottam, Tim; Kiely, David G.; Wong, Ju-Ming; Wharton, Simon; Varcoe, Richard; Siddons, Tom; Spivey, Alan C.; Hall, K.; Giże, A. P.

doi:10.1159/000083502

Cited by 42 publications

(26 citation statements)

References 28 publications

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“…Although it is possible that this variable influenced the statistical analysis independent of NO, this is an unlikely scenario. First, the use of a ratio between a biomarker and urine Cr is a standard method to adjust for urinary dilution (28)(29)(30)(31). Second, in multivariate analyses that included estimated GFR, baseline urine NO/Cr remained highly predictive of better outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…The Cr results obtained were also used to evaluate urine desmosine in these patients; those results have been reported elsewhere (27). The ratio of urine NO to urine Cr (NO/Cr) was used in the statistical analyses to control for urine dilution, a standard method when evaluating urine biomarkers (28)(29)(30)(31). Analyses using urine NO without Cr correction were performed for comparison.…”

Section: No and Cr Measurementsmentioning

confidence: 99%

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Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

McClintock

Ware

Eisner

et al. 2007

Am J Respir Crit Care Med

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Rationale: Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI). Objectives: We tested two hypotheses in patients with ALI: (1 ) higher levels of urine NO would be associated with worse clinical outcomes, and (2 ) ventilation with lower VT would reduce urine NO as a result of less stretch injury. Methods: Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg VT ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr). Results: Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure-free days (mean increase, 2.3 d) on multivariate analysis (p Ͻ 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg VT group (p ϭ 0.04). Conclusions: Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg VT strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI.

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Section: Discussionmentioning

confidence: 99%

Section: No and Cr Measurementsmentioning

confidence: 99%

Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

McClintock

Ware

Eisner

et al. 2007

Am J Respir Crit Care Med

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“…A recent study has shown a decrease in nitric oxide (NO) production after intravenous injection of L -arginine, a precursor for NO synthesis, in patients with primary PH, suggesting a possibility of impaired NO-mediated signaling [1]. Since impairment of NO-mediated signaling is considered as one of the causes of PH during the imbalance between endothelial mediators with opposing actions on pulmonary vasculature, inhaled NO has been used in the treatment of patients with PH.…”

Section: Introductionmentioning

confidence: 99%

Genistein, a Phytoestrogen, Attenuates Monocrotaline-Induced Pulmonary Hypertension

Homma

Morio²,

Takahashi³

et al. 2006

Respiration

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Background: Pulmonary hypertension is characterized by high pulmonary blood pressure, vascular remodeling, and right ventricular hypertrophy. Although recent studies suggest that an imbalance between endothelial mediators on pulmonary vasculature may contribute to the development of pulmonary hypertension, the pathogenesis is not fully understood and the treatment of pulmonary hypertension is still unresolved. Objective: The purpose of this study was to investigate whether genistein, a phytoestrogen derived from soybean, would prevent the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. Hemodynamic parameters of catheterized rats and morphological feature of lungs were evaluated among MCT-treated rats receiving or not receiving genistein. Furthermore, examination of expression in endothelial nitric oxide synthase and endothelin-1 peptide level was performed. Methods: Daily supplementation with either genistein (0.2 mg/kg) or vehicle was started 2 days prior to a single-dose injection of MCT (60 mg/kg). On day 28, rats underwent catheterization, and right ventricular hypertrophy and morphological features were assessed. Furthermore, endothelial nitric oxide synthase and endothelin-1 were examined by Western blot analysis and radioimmunoassay, respectively, in homogenated lungs. Results: In rats that received daily supplementation of genistein, mean pulmonary arterial pressure was significantly reduced, whereas mean systemic arterial pressure and heart rate were unaltered compared with MCT control rats on day 28 after MCT injection. Right ventricular hypertrophy, medial wall thickness of pulmonary arteries corresponding to the terminal bronchioles, and the degree of neomuscularization of more distal arteries were less severe in genistein-treated rats. Genistein supplementation improved MCT-induced downregulation of expression of endothelial nitric oxide synthase in the lungs. However, endothelin-1 peptide levels did not differ among all groups of lungs. Conclusions: We conclude that daily supplementation of genistein potently attenuates MCT-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling in rats. The underlying mechanism responsible for this effect may be partly related to the restoration of a decreased expression of endothelial nitric oxide synthase.

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“…These mechanisms are mediated by 1 or more molecular and cellular processes, including the following: reduced prostacyclin availability caused by diminished endothelial cell prostacyclin synthase activity 25 ; elevated endothelin levels resulting from enhanced production and reduced pulmonary clearance [26][27][28] ; decreased nitric oxide synthase expression 29,30 ; elevated plasma levels and low platelet 5-hydoxytryptamine levels 31 ; down-regulation of voltage-gated potassium (eg, Kv1.5) channels of pulmonary vascular smooth muscle cells 32,33 ; activity of autoantibodies and proinflammatory cytokines 34,35 ; and prothrombotic states arising from endothelial, coagulation, and fibrinolytic cascade and platelet dysfunction. [36][37][38][39] These abnormalities give rise to a predisposition to vasoconstriction over vasodilation of the pulmonary vascu-FIGURE 1.…”

Section: Molecular and Cellular Mechanismsmentioning

confidence: 99%

Pulmonary Hypertension: Diagnosis and Management

McGoon

Kane

2009

Mayo Clinic Proceedings

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Pulmonary arterial hypertension is a progressive, symptomatic, and ultimately fatal disorder for which substantial advances in treatment have been made during the past decade. Effective management requires timely recognition and accurate diagnosis of the disorder and appropriate selection among therapeutic alternatives. Despite progress in treatment, obstacles remain that impede the achievement of optimal outcomes. The current article provides an overview of the pathobiologic mechanisms of pulmonary arterial hypertension, including genetic substrates and molecular and cellular mechanisms, and describes the clinical manifestations and classification of pulmonary arterial hypertension. The article also reviews established approaches to evaluation and treatment, with emphasis on the appropriate application of calcium channel blockers, prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors. In addition, the authors discuss unresolved issues that may complicate patient management, such as the clinical importance of mild or exercise-related pulmonary arterial hypertension, and they identify avenues by which treatment may advance in the future through the use of combination treatment, outcomes assessment, and exploration of alternative pharmacologic strategies. Mayo Clin Proc. 2009;84(2):191-2075-HTT = 5-hydroxytryptamine transporter; BMPR2 = bone morphogenetic protein receptor, type II; FDA = Food and Drug Administration; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PASP = pulmonary arterial systolic pressure; PCWP = pulmonary capillary wedge pressure; PDE5 = phosphodiesterase 5; PH = pulmonary hypertension; TGF-β β β β β = transforming growth factor β β β β β; WHO = World Health Organization T he diagnosis, management, and pathobiologic mechanisms of pulmonary arterial hypertension (PAH) have been of intense interest during the past decade, in large part because of the development of effective treatments that have enhanced the outcome for patients. In the absence of effective treatments, patients with PAH had a median life expectancy of only 2.8 years. Current approaches to the evaluation and management of PAH and to the understanding of the underlying pathophysiologic mechanisms of this condition have been well outlined in recent reviews.

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Decreased Whole Body Endogenous Nitric Oxide Production in Patients with Primary Pulmonary Hypertension

Cited by 42 publications

References 28 publications

Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

Genistein, a Phytoestrogen, Attenuates Monocrotaline-Induced Pulmonary Hypertension

Pulmonary Hypertension: Diagnosis and Management

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