Nitric oxide and pulmonary arterial hypertension

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Abstract

The pathogenesis of pulmonary arterial hypertension remains undefined. Changes in the expression and effects mediated by a number of vasoactive factors have been implicated to play a role in the onset and progression of the disease. The source of many of these mediators, such as nitric oxide (NO), prostacyclin and endothelin-1 (ET-1), is the pulmonary endothelium. This article focus in the role of nitric oxide in PAH, reviewing the evidence for its involvement in regulation of pulmonary a vascular tone under physiological conditions, the mechanisms by which it can contribute to the pathological changes seen in PAH and strategies for the use of NO as a therapy for treatment of the disease.

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The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.

Robert F. Furchgott, John Zawadzki (1980)

Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.

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Survival in patients with primary pulmonary hypertension. Results from a national prospective registry.

G D'Alonzo, R Barst, S. Ayres … (1991)

To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. Registry with prospective follow-up. Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute. Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. At diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals. The estimated median survival of these patients was 2.8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.

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Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).

Raymond Benza, Dave Miller, Mardi Gomberg-Maitland … (2010)

Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. A quantitative survival prediction tool has not been established for research or clinical use. Data from 2716 patients with PAH enrolled consecutively in the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. We identified independent prognosticators of survival and derived a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0% (95% confidence interval [CI], 89.9 to 92.1). In a multivariable analysis with Cox proportional hazards, variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units (hazard ratio [HR], 4.1; 95% CI, 2.0 to 8.3), PAH associated with portal hypertension (HR, 3.6; 95% CI, 2.4 to 5.4), modified New York Heart Association/World Health Organization functional class IV (HR, 3.1; 95% CI, 2.2 to 4.4), men >60 years of age (HR, 2.2; 95% CI, 1.6 to 3.0), and family history of PAH (HR, 2.2; 95% CI, 1.2 to 4.0). Renal insufficiency, PAH associated with connective tissue disease, functional class III, mean right atrial pressure, resting systolic blood pressure and heart rate, 6-minute walk distance, brain natriuretic peptide, percent predicted carbon monoxide diffusing capacity, and pericardial effusion on echocardiogram all predicted mortality. Based on these multivariable analyses, a prognostic equation was derived and validated by bootstrapping technique. We identified key predictors of survival based on the patient's most recent evaluation and formulated a contemporary prognostic equation. Use of this tool may allow the individualization and optimization of therapeutic strategies. Serial follow-up and reassessment are warranted. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.

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Author and article information

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Adrian H. Chester

Journal

Journal ID (nlm-ta): Glob Cardiol Sci Pract

Journal ID (iso-abbrev): Glob Cardiol Sci Pract

Journal ID (publisher-id): GCSP

Journal ID (pmc): GCSP

Title: Global Cardiology Science & Practice

Publisher: Magdi Yacoub Heart Foundation (UK )

ISSN (Electronic): 2305-7823

Publication date (Electronic, pub): 30 June 2017

Publication date (Electronic, collection): 30 June 2017

Volume: 2017

Issue: 2

Electronic Location Identifier: 14

Affiliations

[1 ]National Heart & Lung Institute, Imperial College London, Heart Science Centre , Harefield, Middlesex, UB9 6JH, United Kingdom

[2 ]School of Medical Sciences, Manchester Cancer Research Centre, University of Manchester , Wilmslow Road, Manchester, M20 4QL, United Kingdom

Article

Publisher ID: gcsp.2017.14

DOI: 10.21542/gcsp.2017.14

PMC ID: 5871404

PubMed ID: 29644226

SO-VID: a01e4f8b-294c-40fd-832f-9dfe1de5d881

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This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

Nitric oxide and pulmonary arterial hypertension

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Most cited references 89

The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.

Survival in patients with primary pulmonary hypertension. Results from a national prospective registry.

Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).

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