This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jaimes, E. A. Articles by Raij, L. Search for Related Content PubMed PubMed Citation Articles by Jaimes, E. A. Articles by Raij, L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE HYDROGEN PEROXIDE NITRIC OXIDE Related Collections Oxidant stress Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors Pathophysiology Hypertension - basic studies Ischemic biology - basic studies

(Hypertension. 2001;38:877.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Effects of the Reactive Oxygen Species Hydrogen Peroxide and Hypochlorite on Endothelial Nitric Oxide Production

Edgar A. Jaimes; Charles Sweeney; Leopoldo Raij

From the Nephrology and Hypertension Section, Veterans Administration Medical Center; and University of Minnesota, Minneapolis, Minn.

Correspondence and reprint requests to Leopoldo Raij, MD, Nephrology and Hypertension Section IIIJ, Veterans Administration Medical Center, 1 Veterans Dr, Minneapolis, MN 55417. E-mail raijx001{at}tc.umn.edu

Abstract—— Reactive oxygen species (ROS) hydrogen peroxide (H₂O₂) and hypochlorite (HOCl) participate in the pathogenesis of ischemia/reperfusion injury, inflammation, and atherosclerosis. Both NO and ROS are important modulators of vascular tone and architecture and of adhesive interactions between leukocytes, platelets, and vascular endothelium. We studied the effect of H₂O₂ and HOCl on receptor-dependent (bradykinin [10^-6 mol/L] and ADP [10^-4 mol/L]) and receptor-independent mechanisms (calcium ionophore A23187 [10^-6 mol/L]) of NO production by porcine aortic endothelial cells (ECs). Changes in the level of EC cGMP (the second messenger of NO) were used as a surrogate of NO production. EC cGMP increased 300% in response to bradykinin and A23187 and 200% in response to ADP. Exposure of ECs to H₂O₂ (50 µmol/L) for 30 minutes significantly impaired cGMP levels in response to ADP, bradykinin, and the receptor-independent NO agonist A23187. In contrast, preincubation with HOCl (50 µmol/L) impaired cGMP production only in response to ADP and bradykinin but not A23187. These concentrations of H₂O₂ and HOCl did not result in increased EC lethality as assessed by lactate dehydrogenase release. Neither H₂O₂ nor HOCl affected EC cGMP production in response to NO donor sodium nitroprusside, which suggests that guanylate cyclase is resistant to these oxidants. We also demonstrated that neither H₂O₂ nor HOCl affects endothelial NO synthase (eNOS) catalytic activity as measured by conversion of L-arginine to L-citrulline in EC homogenates supplemented with eNOS cofactors. The present studies show that H₂O₂ impairs NO production in response to both receptor-dependent and receptor-independent agonists and that these effects are due, at least in part, to inactivation of eNOS cofactors, whereas HOCl inhibits NO production by interfering with receptor-operated mechanisms at the level of the cell membrane. Concentrations of H₂O₂ and HOCl used in the present studies have been shown to be generated in vivo during inflammation and ischemia/reperfusion. Therefore, we infer that these effects of H₂O₂ and HOCl on EC NO production may contribute to disregulated vascular tone and altered leukocyte-EC interactions that occur in vascular injury as a result of those causes in which ROS generation is involved.

Key Words: endothelium • nitric oxide • reactive oxygen species • atherosclerosis • inflammation

This article has been cited by other articles:

				T. Radovits, J. Zotkina, L.-N. Lin, T. Bomicke, R. Arif, D. Gero, E. M. Horvath, M. Karck, C. Szabo, and G. Szabo Poly(ADP-Ribose) Polymerase Inhibition Improves Endothelial Dysfunction Induced by Hypochlorite Experimental Biology and Medicine, October 1, 2007; 232(9): 1204 - 1212. [Abstract] [Full Text] [PDF]

				M. J. Haurani and P. J. Pagano Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovasc Res, September 1, 2007; 75(4): 679 - 689. [Abstract] [Full Text] [PDF]

				P. H. McNulty, B. J. Robertson, M. A. Tulli, J. Hess, L. A. Harach, S. Scott, and L. I. Sinoway Effect of hyperoxia and vitamin C on coronary blood flow in patients with ischemic heart disease J Appl Physiol, May 1, 2007; 102(5): 2040 - 2045. [Abstract] [Full Text] [PDF]

				N. Ardanaz and P. J. Pagano Hydrogen peroxide as a paracrine vascular mediator: regulation and signaling leading to dysfunction. Experimental Biology and Medicine, March 1, 2006; 231(3): 237 - 251. [Abstract] [Full Text] [PDF]

				T. Suvorava, N. Lauer, S. Kumpf, R. Jacob, W. Meyer, and G. Kojda Endogenous Vascular Hydrogen Peroxide Regulates Arteriolar Tension In Vivo Circulation, October 18, 2005; 112(16): 2487 - 2495. [Abstract] [Full Text] [PDF]

				R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]

				C. Di Filippo, F. Rossi, E. Ongini, P. Del Soldato, M. Perretti, and M. D'Amico The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1 J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1133 - 1141. [Abstract] [Full Text] [PDF]

				R. Komers and S. Anderson Paradoxes of nitric oxide in the diabetic kidney Am J Physiol Renal Physiol, June 1, 2003; 284(6): F1121 - F1137. [Abstract] [Full Text] [PDF]

				H. Cai, Z. Li, M. E. Davis, W. Kanner, D. G. Harrison, and S. C. Dudley Jr. Akt-Dependent Phosphorylation of Serine 1179 and Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Cooperatively Mediate Activation of the Endothelial Nitric-Oxide Synthase by Hydrogen Peroxide Mol. Pharmacol., February 1, 2003; 63(2): 325 - 331. [Abstract] [Full Text] [PDF]

				D. Galipeau, S. Verma, and J. H. McNeill Female rats are protected against fructose-induced changes in metabolism and blood pressure Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2478 - H2484. [Abstract] [Full Text] [PDF]

				D. M. Galipeau, L. Yao, and J. H. McNeill Relationship among hyperinsulinemia, insulin resistance, and hypertension is dependent on sex Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H562 - H567. [Abstract] [Full Text] [PDF]