Nitric oxide and pulmonary arterial pressures in pulmonary hypertension

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Abstract

Decreased production of vasodilator substances such as nitric oxide (NO) has been proposed as important in development of pulmonary arterial hypertension (PAH). We hypothesize that NO measured over time serves as a non invasive marker of severity of PAH and response to therapy. We prospectively and serially measured exhaled NO and carbon monoxide (CO), a vasodilator and anti-inflammatory product of heme oxygenases, in 17 PAH patients in conjunction with hemodynamic parameters over 2 years. Although pulmonary artery pressures and NO were similar in all patients at entry to the study, NO increased in the 12 individuals who survived to complete the study, and correlated with change in pulmonary artery pressures. In contrast, CO did not change or correlate with hemodynamic parameters. Investigation of NO–oxidant reaction products in PAH in comparison to controls suggests that NO synthesis is impaired in the lung and that reactive oxygen species may be involved in the pathophysiology of pulmonary hypertension. Endogenous NO is inversely related to pulmonary artery pressure in PAH, with successful therapy of PAH associated with increase in NO.

Introduction

Pulmonary arterial hypertension (PAH) is a rare disease of unknown etiology leading to the development of severe precapillary pulmonary hypertension characterized by impaired regulation of both pulmonary hemodynamics and vascular growth [1]. PAH may be associated with known diseases, such as collagen vascular diseases and portal hypertension, but, in the absence of an identifiable etiology, is classified as primary pulmonary hypertension (PPH, PAH class 1.1) [2]. Abnormalities in vasodilator substances such as nitric oxide (NO) have been proposed as important in the development of PAH [3], and vasodilator therapy has been shown to prolong survival in these patients [4]. Other experimental data suggest that carbon monoxide (CO), endogenously produced through heme oxygenases and having significant antiproliferative and vasodilatory effects on the pulmonary circulation, may also be involved in the pathogenesis of PAH [5], [6], [7], [8], [9], [10]. Current clinical markers of prognosis include hemodynamic variables, including degree of pulmonary hypertension and the function of the right ventricle [11]; however, noninvasive quantitative tests for pulmonary hypertension, monitoring disease progression and evaluation of response to therapy, are not available.

We and others have previously shown that individuals with PPH have lower than normal exhaled NO and that NO production in the lung is inversely related to the degree of pulmonary hypertension [12]. Further, individuals with PAH have an increase in exhaled NO concomitant with a decrease in pulmonary artery pressure after initiation of vasodilator therapy with the prostacyclin epoprostenol [13]. We hypothesized that serial measurement of NO over time may serve as a noninvasive marker of severity of PAH and response to therapy.

To evaluate the relative roles of NO and CO in PAH, we prospectively and serially determined exhaled NO and CO in 17 individuals with pulmonary hypertension in conjunction with hemodynamic parameters over a 2-year period. To investigate the role of oxidant species in the mechanisms that decrease NO, NO–oxidant reaction products were assessed noninvasively by collection of serum and exhaled breath condensate from PAH patients and healthy control individuals. Exhaled breath condensate has been increasingly used as a noninvasive method to sample the lower airway fluid with measurable characteristics that differ in health and disease [14]. Specifically, alterations in exhaled breath condensate levels of several NO reaction products have been demonstrated in tobacco use [15] and inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, and pneumonia [16], [17], [18], [19]. In the context of a pro-inflammatory environment in PAH lungs [12], [20], we hypothesized that NO produced in the lungs of PAH patients is increasingly consumed by reactive oxygen species, such as superoxide.

Section snippets

Methods

Individuals with PAH were identified for enrollment into the prospective study if they met the NIH registry diagnostic criteria for pulmonary hypertension [21] and were classified according to the World Health Organization criteria as PAH class 1 [22]. Specifically, participation was restricted to patients who had pulmonary hypertension determined by right heart catheterization as part of their standard care; i.e., right heart catheterization was not done for research purposes. All individuals

Clinical characteristics of patients in the prospective study

Seventeen PAH patients were enrolled in the study; 5 died during the study and 12 completed the study. Table 1, Table 2 describe the characteristics of the study population and hemodynamic measures determined at screening and during times 1 to 3 of the study. Associated causes of PAH were scleroderma (n = 3), portopulmonary hypertension (n = 4), Eisenmenger's syndrome (n = 1), and sarcoid vasculitis (n = 1). Mean time from initial diagnostic cardiac catheterization/initiation of therapy to

Discussion

Ever since endothelium-derived relaxing factor was pharmacologically defined as identical to NO activity, NO has been proposed as the major physiologic regulator of blood vessel tone [29], [30], [31]. Here, we provide evidence that endogenous NO production is closely related to pulmonary artery pressures in the pathologic state of pulmonary hypertension in the human lung. It is also important to note that the majority of patients in this study were on prostacyclin vasodilator therapy. The

Acknowledgments

We thank K. Stelmach for help with patient recruitment. This work was supported by NIH Grants HL60917, HL04265, and HL68863 and, in part, by Public Health Service Research Grant MO1-RR018390.

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