© 2005 American Thoracic Society doi: 10.1164/rccm.2505009
A Urinary Test for Pulmonary Arterial Hypertension?Cleveland Clinic Foundation, Cleveland, Ohio Abnormality of nitric oxide (NO) production has long been a primary hypothesis for the pathophysiology of pulmonary arterial hypertension (PAH). Animal models of pulmonary hypertension, mice genetically deficient in NO synthases (NOS), and complementation studies with gene transfer of NOS provide abundant evidence for the concept that NO is a critical determinant of pulmonary vascular tone (1, 2). However, human studies measuring exhaled NO have provided conflicting results on whether or not NO in patients with PAH is less than in healthy control subjects. In this issue of the Journal, Girgis and colleagues (pp. 352–357) provide definitive evidence that patients with PAH have reduced NO in the lung and that successful therapy increases exhaled NO (3). In elegant studies based on measurement of exhaled NO at varying airflow rates and the two-compartment model of pulmonary NO exchange in the lung, they provide new information on how NO production is affected in select regions of the lung, and localize impaired NO production to the airway wall compartment. Similar to previously noted effects of prostacyclin therapy on exhaled NO (4), exhaled NO in patients with PAH increased after endothelin-A receptor blockade with bosentan, therapy that enhances the release of NO and may also reduce oxidative consumption of NO (5, 6). In this context, one important limitation of exhaled NO studies is the inability to determine the mechanisms producing the observed effects, because reduced NO levels do not necessarily identify decrease in NO synthesis. NO levels reflect a steady state between synthesis and consumption of NO, and several studies have identified increased oxidant reactions in PAH lungs, which almost certainly lead to increased NO consumption (7, 8). Nevertheless, improvement in exhaled NO values in patients on therapy is clearly related to improvements in pulmonary vascular resistance (3, 4, 8). An important distinction from previous studies is the complete evaluation in Girgis and colleagues' experiments of whole-body NO metabolism in patients with PAH. Exhaled NO, stable oxidation end-products of NO in serum and urine, endogenous inhibitors of NOS, and the NOS substrate arginine were determined at baseline before therapy, and 3 months after initiation of therapy. The NOS enzymes use the terminal guanidine nitrogen of L-arginine as the precursor for NO, which is oxidized to the stable nitrogen oxides, nitrite and nitrate. Nitrate is the predominant end-product in the circulation, because nitrite is rapidly oxidized to nitrate via hemoglobin. Although urinary nitrate excretion depends on renal function, nitrate intake, and the presence of nitrate-producing bacteria, it is possible to evaluate endogenous NO production by measuring serum or urine nitrogen oxides under conditions of strict dietary nitrate regulation alone, or in combination with administration of stable nuclide-labeled arginine. In 1981, Green and colleagues (9) first described endogenous nitrate biosynthesis in healthy men by measuring excreted urine nitrate. However, surprisingly little is known about how NO metabolism varies in human pathophysiology, and the investigation of whole-body NO metabolism in human subjects with pulmonary hypertension is limited to three studies, one of which includes the current study by Girgis and colleagues (3, 10, 11). Castillo (10) first showed alterations of urinary nitrate excretion in acute persistent pulmonary hypertension of newborns. Using an infusion of the stable nuclide of arginine (L-[15N]2-arginine), Castillo found a marked increase in urine 15N-nitrate, and in the rate of conversion of arginine to NO, with resolution of pulmonary hypertension (10). In a similar study of adult patients with PAH, urinary excretion of 15N-nitrite and 15N-nitrate of patients with PAH was found to be a small fraction of that in healthy control subjects (11). The study of Girgis and colleagues confirms that patients with PAH have reduced urine nitrate as compared with control subjects, and provides evidence that urine nitrate increases in subjects after therapy. A profound increase in NO metabolite excretion was found, which was unrelated to creatinine clearance (3, 10, 11), excluding the possibility that better renal function, with reduction of pulmonary artery pressures, led to higher nitrate clearance. Thus, this study adds substantially to the growing body of evidence of abnormalities in the arginine–NO pathway in PAH (8, 10–15). Specifically, mechanisms that reduce NO synthesis by limiting arginine availability to the enzyme have also been previously demonstrated in patients with PAH, including increased endogenous inhibitory methylated arginines (3, 13) and increased arginase, a urea cycle enzyme that converts arginine to urea and ornithine (12, 14, 15). Although Girgis and colleagues did not measure arginase activity, plasma citrulline was reduced in patients with PAH in their study, which may imply alterations in NOS or urea cycle enzyme reactions. A logical conclusion from these studies is that altered whole-body arginine–NO metabolism is a fundamental process intrinsic to the pathophysiology leading to pulmonary hypertension. If there are systemic abnormalities of the arginine–NO pathway, patients with PAH might also have alterations in systemic vascular reactivity. In fact, a relation between systemic vascular reactivity, pulmonary hypertension, and NO has been recently reported (16). It remains to be determined to what extent quantitative relationships between exhaled NO, urine nitrate, and pulmonary arterial pressures apply to an individual who is undergoing treatment with different forms of therapy over time. However, there is now sufficient accumulated evidence to support exhaled-breath NO studies in the monitoring of response to therapy in patients with PAH, and perhaps the measurement of nitrate in urine. FOOTNOTES Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject in this manuscript. REFERENCES
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