Am. J. Respir. Crit. Care Med., Volume 158, Number 3, September 1998, 917-923

Biochemical Reaction Products of Nitric Oxide as Quantitative Markers of Primary Pulmonary Hypertension

F. TAKAO KANEKO, ALEJANDRO C. ARROLIGA, RAED A. DWEIK, SUZY A. COMHAIR, DANIEL LASKOWSKI, RITA OPPEDISANO, MARY JANE THOMASSEN, and SERPIL C. ERZURUM

Departments of Pulmonary and Critical Care Medicine and Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio

Primary pulmonary hypertension (PPH) is a rare and fatal disease of unknown etiology. Inflammatory oxidant mechanisms and deficiency in nitric oxide (NO) have been implicated in the pathogenesis of pulmonary hypertension. In order to investigate abnormalities in oxidants and antioxidants in PPH, we studied intrapulmonary NO levels, biochemical reaction products of NO, and antioxidants (glutathione [GSH], glutathione peroxidase [GPx], and superoxide dismutase [SOD]) in patients with PPH (n = 8) and healthy controls (n = 8). Intrapulmonary gases and fluids were sampled at bronchoscopy. Pulmonary hypertension was determined by right-heart catheterization. NO and biochemical reaction products of NO in the lung were decreased in PPH patients in comparison with healthy controls (NO [ppb] in airway gases: control, 8 ± 1; PPH, 2.8 ± 0.9; p = 0.016; and NO products [µM] in bronchoalveolar lavage fluid [BALF]: control, 3.3 ± 1.05; PPH, 0.69 ± 0.21; p = 0.03). However, GSH in the lungs of PPH patients was higher than in those of controls (GSH [µM] in BALF: 0.55 ± 0.04; PPH, 0.9 ± 0.1; p = 0.015). SOD and GPx activities were similar in the two groups (p  0.50). Biochemical reaction products of NO were inversely correlated with pulmonary artery pressures (R = 0.713; p = 0.047) and with years since diagnosis of PPH (R = 0.776; p = 0.023). NO reaction products are formed through interactions between oxidants and NO, with the end products of reaction dependent upon the relative levels of the two types of molecules. The findings of the study therefore show that NO and oxidant reactions in the lung are related to the increased pulmonary artery pressures in PPH.

This article has been cited by other articles:

				R. F. Machado Amino acids and the erythrocyte under stress? Blood, January 1, 2008; 111(1): 2 - 2. [Full Text] [PDF]

				A. Sasaki, S. Doi, S. Mizutani, and H. Azuma Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1480 - L1487. [Abstract] [Full Text] [PDF]

				W. Xu, T. Koeck, A. R. Lara, D. Neumann, F. P. DiFilippo, M. Koo, A. J. Janocha, F. A. Masri, A. C. Arroliga, C. Jennings, et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells PNAS, January 23, 2007; 104(4): 1342 - 1347. [Abstract] [Full Text] [PDF]

				R. A. Dweik The lung in the balance: arginine, methylated arginines, and nitric oxide Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L15 - L17. [Full Text] [PDF]

				I. Horvath, J. Hunt, P. J. Barnes, and On behalf of the ATS/ERS Task Force on Exhaled Bre Exhaled breath condensate: methodological recommendations and unresolved questions Eur. Respir. J., September 1, 2005; 26(3): 523 - 548. [Abstract] [Full Text] [PDF]

				R. E. Girgis, H. C. Champion, G. B. Diette, R. A. Johns, S. Permutt, and J. T. Sylvester Decreased Exhaled Nitric Oxide in Pulmonary Arterial Hypertension: Response to Bosentan Therapy Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 352 - 357. [Abstract] [Full Text] [PDF]

				C. R. Morris, G. J. Kato, M. Poljakovic, X. Wang, W. C. Blackwelder, V. Sachdev, S. L. Hazen, E. P. Vichinsky, S. M. Morris Jr, and M. T. Gladwin Dysregulated Arginine Metabolism, Hemolysis-Associated Pulmonary Hypertension, and Mortality in Sickle Cell Disease JAMA, July 6, 2005; 294(1): 81 - 90. [Abstract] [Full Text] [PDF]

				J. P. Khoo, L. Zhao, N. J. Alp, J. K. Bendall, T. Nicoli, K. Rockett, M. R. Wilkins, and K. M. Channon Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension Circulation, April 26, 2005; 111(16): 2126 - 2133. [Abstract] [Full Text] [PDF]

				R A Dweik Nitric oxide, hypoxia, and superoxide: the good, the bad, and the ugly! Thorax, April 1, 2005; 60(4): 265 - 267. [Full Text] [PDF]

				R. Bowers, C. Cool, R. C. Murphy, R. M. Tuder, M. W. Hopken, S. C. Flores, and N. F. Voelkel Oxidative Stress in Severe Pulmonary Hypertension Am. J. Respir. Crit. Care Med., March 15, 2004; 169(6): 764 - 769. [Abstract] [Full Text] [PDF]

				J. P. Cooke A Novel Mechanism for Pulmonary Arterial Hypertension? Circulation, September 23, 2003; 108(12): 1420 - 1421. [Full Text] [PDF]

				C. R. Morris, S. M. Morris Jr., W. Hagar, J. van Warmerdam, S. Claster, D. Kepka-Lenhart, L. Machado, F. A. Kuypers, and E. P. Vichinsky Arginine Therapy: A New Treatment for Pulmonary Hypertension in Sickle Cell Disease? Am. J. Respir. Crit. Care Med., July 1, 2003; 168(1): 63 - 69. [Abstract] [Full Text] [PDF]

				V. L. Kinnula and J. D. Crapo Superoxide Dismutases in the Lung and Human Lung Diseases Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1600 - 1619. [Abstract] [Full Text] [PDF]

				M. Ameen, I. Ahmad, S. Musthapa, M. A. Baig, R. Mishra, and Q. Rahman Differential responses of rat alveolar macrophages to carpet dust in vitro Human and Experimental Toxicology, May 1, 2003; 22(5): 263 - 270. [Abstract] [PDF]

				S. Mehta Sildenafil for Pulmonary Arterial Hypertension: Exciting, But Protection Required Chest, April 1, 2003; 123(4): 989 - 992. [Full Text] [PDF]

				A. L. Rafanan, J. A. Golish, D. S. Dinner, L. K. Hague, and A. C. Arroliga Nocturnal Hypoxemia Is Common in Primary Pulmonary Hypertension Chest, September 1, 2001; 120(3): 894 - 899. [Abstract] [Full Text] [PDF]

				S. A. KHARITONOV and P. J. BARNES Exhaled Markers of Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 2001; 163(7): 1693 - 1722. [Full Text] [PDF]

				R. S. Sprague, A. H. Stephenson, M. L. Ellsworth, C. Keller, and A. J. Lonigro Impaired Release of ATP from Red Blood Cells of Humans with Primary Pulmonary Hypertension Experimental Biology and Medicine, May 1, 2001; 226(5): 434 - 439. [Abstract] [Full Text]

				R. A. Dweik, D. Laskowski, M. Özkan, C. Farver, and S. C. Erzurum High Levels of Exhaled Nitric Oxide (NO) and NO Synthase III Expression in Lesional Smooth Muscle in Lymphangioleiomyomatosis Am. J. Respir. Cell Mol. Biol., April 1, 2001; 24(4): 414 - 418. [Abstract] [Full Text]

				N. NAGAYA, M. UEMATSU, H. OYA, N. SATO, F. SAKAMAKI, S. KYOTANI, K. UENO, N. NAKANISHI, M. YAMAGISHI, and K. MIYATAKE Short-term Oral Administration of L-Arginine Improves Hemodynamics and Exercise Capacity in Patients with Precapillary Pulmonary Hypertension Am. J. Respir. Crit. Care Med., March 15, 2001; 163(4): 887 - 891. [Abstract] [Full Text]

				B. Raychaudhuri, R. Dweik, M. J. Connors, L. Buhrow, A. Malur, J. Drazba, A. C. Arroliga, S. C. Erzurum, M. S. Kavuru, and M. J. Thomassen Nitric Oxide Blocks Nuclear Factor-kappa B Activation in Alveolar Macrophages Am. J. Respir. Cell Mol. Biol., September 1, 1999; 21(3): 311 - 316. [Abstract] [Full Text]

				H. L. Reeve, S. L. Archer, M. Soper, and E. K. Weir Dexfenfluramine increases pulmonary artery smooth muscle intracellular Ca2+, independent of membrane potential Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L662 - L666. [Abstract] [Full Text] [PDF]