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

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          Impaired pulmonary release of nitric oxide (NO) is one of the characteristic phenotypic changes of vascular cells in pulmonary hypertension. The aim of this study was to determine nitric oxide synthase (NOS)-dependent whole body NO production in patients with primary pulmonary hypertension. NOS-dependent whole body NO production was assessed by giving an intravenous infusion of L-[<sup>15</sup>N]<sub>2</sub>-arginine (50 µmol/min for 30 min) and measuring isotopic urinary enrichment of <sup>15</sup>N-nitrite and <sup>15</sup>N-nitrate. Four female patients with no signs of infection were recruited and compared with 6 age-matched control subjects. Mean 12-hour excretion of <sup>15</sup>N-nitrite and <sup>15</sup>N-nitrate in the total urine over 36 h was smaller in patients than in control subjects (57.2 ± 27.6 vs. 229.1 ± 65.2 nmol/mmol creatinine, p< 0.01, Mann-Whitney U test, respectively). Neither mean 12-hour excretion of <sup>14</sup>N-nitrite and <sup>14</sup>N-nitrate (51.6 ± 10.0 vs. 72.4 ± 10.0 µmol/mmol creatinine, p = 0.3) nor glomerular filtration rates (84.5 ± 15.8 vs. 129.7 ± 16.0 ml/min, p = 0.1) were different between patients and control subjects. Our results suggest that either basal NOS-dependent whole body NO production is impaired or excess NO metabolism occurs in patients with primary pulmonary hypertension.

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          Most cited references 10

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

          Pulmonary hypertension is characterized by abnormal thickening of the pulmonary arteries and increased pulmonary vascular resistance. Nitric oxide is a potent endothelium-derived vasorelaxant substance and an inhibitor of smooth-muscle-cell growth. Nitric oxide is produced in various cell types by the action of an enzyme, nitric oxide synthase. We compared the expression of endothelial nitric oxide synthase in the lungs of control subjects with that in the lungs of patients with pulmonary hypertension. We investigated the expression of endothelial nitric oxide synthase by histochemical and immunohistochemical analysis, in situ hybridization, and Northern blot analysis in the lungs of 22 patients with plexogenic pulmonary arteriopathy (arteriopathy of grades 4 through 6), 24 patients with secondary pulmonary hypertension (arteriopathy of grades 1 through 3), and 23 control subjects. In the lungs of the control subjects, nitric oxide synthase was expressed at a high level in the vascular endothelium of all types of vessels and in the pulmonary epithelium. In contrast, little or no expression of the enzyme was found in the vascular endothelium of pulmonary arteries with severe histologic abnormalities (i.e., plexiform lesions) in patients with pulmonary hypertension. The intensity of the enzyme immunoreactivity correlated inversely with the severity of histologic changes. There was an inverse correlation between the arterial expression of the enzyme and total pulmonary resistance in patients with plexogenic pulmonary arteriopathy (r = -0.766, P = 0.004). Pulmonary hypertension is associated with diminished expression of endothelial nitric oxide synthase. It is possible that decreased expression of nitric oxide synthase may contribute to pulmonary vasoconstriction and to the excessive growth of the tunica media observed in this disease.
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            Myeloperoxidase, a leukocyte-derived vascular NO oxidase.

            Myeloperoxidase (MPO) is an abundant mammalian phagocyte hemoprotein thought to primarily mediate host defense reactions. Although its microbicidal functions are well established in vitro, humans deficient in MPO are not at unusual risk of infection. MPO was observed herein to modulate the vascular signaling and vasodilatory functions of nitric oxide (NO) during acute inflammation. After leukocyte degranulation, MPO localized in and around vascular endothelial cells in a rodent model of acute endotoxemia and impaired endothelium-dependent relaxant responses, to which MPO-deficient mice were resistant. Altered vascular responsiveness was due to catalytic consumption of NO by substrate radicals generated by MPO. Thus MPO can directly modulate vascular inflammatory responses by regulating NO bioavailability.
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              Oxidative stress in severe pulmonary hypertension.

              Severe pulmonary hypertension (PH) occurs in a primary or "unexplained" form and in a group of secondary forms associated with a number of diseases. Because the lung tissue from patients with severe PH demonstrates complex vascular lesions, which contain inflammatory cells, we wondered whether the lung tissue from patients with severe PH was "under oxidative stress." We used immunohistochemistry to localize nitrotyrosine and 8-hydroxy guanosine in the lung tissue sections from patients with primary and secondary PH. In some lung tissue extracts, the eicosanoid metabolites 5-oxo-eicosatetraenoic acid, leukotriene B4 5-hydroxyeicosatetraenoic acid (HETE), 12-HETE, and 15-HETE were measured using mass spectroscopy, and superoxide dismutase amount and activity were measured. Nitrotyrosine expression was ubiquitous in all PH lungs, and 5-oxo-eicosatetraenoic acid and HETE levels were elevated in the lungs of patients with severe PH but not in those lungs that were from the patients with severe PH treated chronically with prostacyclin. We conclude that indeed the lungs from patients with severe PH are under oxidative stress and that chronic prostacyclin infusion has an antiinflammatory effect on the lung tissue.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2005
                13 April 2005
                : 42
                : 2
                : 133-136
                aDivision of Clinical Sciences (South), University of Sheffield, Royal Hallamshire Hospital, and bRespiratory Function Unit, Sheffield Teaching Hospital NHS Trust, Sheffield, cAstraZeneca R&D Charnwood, Loughborough, dDepartment of Chemistry, South Kensington Campus, Imperial College, London, and eManchester Medical Mass Spectrometry Facility, Unit A Millbrook Business Centre, Manchester, UK
                83502 J Vasc Res 2005;42:133–136
                © 2005 S. Karger AG, Basel

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                Figures: 1, Tables: 1, References: 18, Pages: 4
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