This Article Full Text Full Text (PDF) 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 Prasad, A. Articles by Quyyumi, A. A. Search for Related Content PubMed PubMed Citation Articles by Prasad, A. Articles by Quyyumi, A. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LOSARTAN POTASSIUM Related Collections ACE/Angiotension receptors Endothelium/vascular type/nitric oxide

(Circulation. 2000;101:2349.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Acute and Chronic Angiotensin-1 Receptor Antagonism Reverses Endothelial Dysfunction in Atherosclerosis

Abhiram Prasad, MB, MRCP; Theresa Tupas-Habib, BS; William H. Schenke, BS; Rita Mincemoyer, RN; Julio A. Panza, MD; Myron A. Waclawin, PhD; Samer Ellahham, MD; Arshed A. Quyyumi, MD, FRCP

From the Cardiology Branch (A.P., W.H.S., R.M., J.A.P., A.A.Q.) and the Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; and Division of Cardiology (T.T.-H., S.E.), Department of Internal Medicine, Washington Hospital Center, Washington, DC.

Correspondence to Arshed A. Quyyumi, MD, National Institutes of Health, Cardiology Branch, NHLBI, Bldg 10, Room 7B15, 10 Center Dr, MSC 1650, Bethesda, MD 20892-1650. E-mail quyyumia{at}nih.gov

Background—The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The present study was performed to determine whether angiotensin-1 (AT₁) receptor inhibition improves endothelial dysfunction.

Methods and Results—In the femoral circulation of 19 patients with atherosclerosis and of 9 control subjects, we studied microvascular responses to reactive hyperemia, angiotensin II, acetylcholine, and sodium nitroprusside before and after the administration of intra-arterial losartan (10 mg). Femoral artery flow velocity was measured with a Doppler flow wire, and the femoral vascular resistance index (FVRI) was calculated as mean arterial pressure divided by flow velocity. Losartan induced a minor (5.9±2%, P=0.02) reduction in FVRI and inhibited angiotensin II–mediated vasoconstriction in both patient groups (P<0.01). After the administration of losartan, acetylcholine-mediated vasodilation was augmented in patients (44±5% to 58±4% reduction in FVRI with infusion at a rate of 150 µg/min, P<0.001) but not control subjects. Vasodilation during reactive hyperemia was also greater after AT₁ receptor inhibition (P=0.03) in patients, but the response to sodium nitroprusside remained unchanged. In a separate group of 31 patients with atherosclerosis, we investigated the effect of 8 weeks of oral losartan therapy on brachial artery flow-mediated vasodilation with the use of high-resolution ultrasound. Oral losartan therapy improved flow-mediated brachial artery dilation (1.4±0.9% to 3.2±0.8%, P=0.03) but had no effect on the nitroglycerin response. Serum nitrogen oxide levels increased from 21.6±1.7 to 26.7±2.4 µmol/L (P=0.008).

Conclusions—The results of the present study indicate that inhibition of the AT₁ receptor in patients with atherosclerosis reverses endothelial dysfunction by improving NO availability and therefore may have long-term therapeutic benefits.

Key Words: atherosclerosis • angiotensin • nitric oxide • endothelium • receptors • losartan

This article has been cited by other articles:

				M. Kosch, A. Levers, D. Lang, V. Bartels, K. H. Rahn, H. Pavenstadt, and M. Hausberg A randomized, double-blind study of valsartan versus metoprolol on arterial distensibility and endothelial function in essential hypertension Nephrol. Dial. Transplant., July 1, 2008; 23(7): 2280 - 2285. [Abstract] [Full Text] [PDF]

				S. Ashfaq, J. L. Abramson, D. P. Jones, S. D. Rhodes, W. S. Weintraub, W. C. Hooper, V. Vaccarino, R. W. Alexander, D. G. Harrison, and A. A. Quyyumi Endothelial Function and Aminothiol Biomarkers of Oxidative Stress in Healthy Adults Hypertension, July 1, 2008; 52(1): 80 - 85. [Abstract] [Full Text] [PDF]

				S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]

				T. Yamashita, A. Sekiguchi, T. Kato, T. Tsuneda, Y.-k. Iwasaki, K. Sagara, H. Iinuma, H. Sawada, and T. Aizawa Angiotensin type 1 receptor blockade prevents endocardial dysfunction of rapidly paced atria in rats Journal of Renin-Angiotensin-Aldosterone System, September 1, 2007; 8(3): 127 - 132. [Abstract] [PDF]

				T. Godfraind Antioxidant effects and the therapeutic mode of action of calcium channel blockers in hypertension and atherosclerosis Phil Trans R Soc B, December 29, 2005; 360(1464): 2259 - 2272. [Abstract] [Full Text] [PDF]

				S. Takai, D. Jin, M. Muramatsu, K. Kirimura, H. Sakonjo, and M. Miyazaki Eplerenone Inhibits Atherosclerosis in Nonhuman Primates Hypertension, November 1, 2005; 46(5): 1135 - 1139. [Abstract] [Full Text] [PDF]

				J Trevelyan, E W A Needham, A Morris, and R K Mattu Comparison of the effect of enalapril and losartan in conjunction with surgical coronary revascularisation versus revascularisation alone on systemic endothelial function Heart, August 1, 2005; 91(8): 1053 - 1057. [Abstract] [Full Text] [PDF]

				M. Akishita, K. Nagai, H. Xi, W. Yu, N. Sudoh, T. Watanabe, M. Ohara-Imaizumi, S. Nagamatsu, K. Kozaki, M. Horiuchi, et al. Renin-Angiotensin System Modulates Oxidative Stress-Induced Endothelial Cell Apoptosis in Rats Hypertension, June 1, 2005; 45(6): 1188 - 1193. [Abstract] [Full Text] [PDF]

				A. Ceriello, R. Assaloni, R. Da Ros, A. Maier, L. Piconi, L. Quagliaro, K. Esposito, and D. Giugliano Effect of Atorvastatin and Irbesartan, Alone and in Combination, on Postprandial Endothelial Dysfunction, Oxidative Stress, and Inflammation in Type 2 Diabetic Patients Circulation, May 17, 2005; 111(19): 2518 - 2524. [Abstract] [Full Text] [PDF]

				D. Fliser, K.-K. Wagner, A. Loos, D. Tsikas, and H. Haller Chronic Angiotensin II Receptor Blockade Reduces (Intra)Renal Vascular Resistance in Patients with Type 2 Diabetes J. Am. Soc. Nephrol., April 1, 2005; 16(4): 1135 - 1140. [Abstract] [Full Text] [PDF]

				M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response Eur. Heart J., February 2, 2005; 26(4): 363 - 368. [Abstract] [Full Text] [PDF]

				K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, Y.-H. Seo, M. H. Kang, T. H. Ahn, I. S. Choi, and E. K. Shin Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients Circulation, December 14, 2004; 110(24): 3687 - 3692. [Abstract] [Full Text] [PDF]

				A. Prasad and A. A. Quyyumi Renin-Angiotensin System and Angiotensin Receptor Blockers in the Metabolic Syndrome Circulation, September 14, 2004; 110(11): 1507 - 1512. [Full Text] [PDF]

				G. Nickenig Should Angiotensin II Receptor Blockers and Statins Be Combined? Circulation, August 24, 2004; 110(8): 1013 - 1020. [Full Text] [PDF]

				S. A. Phillips, I. Drenjancevic-Peric, J. C. Frisbee, and J. H. Lombard Chronic AT1 receptor blockade alters mechanisms mediating responses to hypoxia in rat skeletal muscle resistance arteries Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H545 - H552. [Abstract] [Full Text] [PDF]

				S. Wassmann, M. Stumpf, K. Strehlow, A. Schmid, B. Schieffer, M. Bohm, and G. Nickenig Interleukin-6 Induces Oxidative Stress and Endothelial Dysfunction by Overexpression of the Angiotensin II Type 1 Receptor Circ. Res., March 5, 2004; 94(4): 534 - 541. [Abstract] [Full Text] [PDF]

				M. E. Widlansky, N. Gokce, J. F. Keaney Jr, and J. A. Vita The clinical implications of endothelial dysfunction J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1149 - 1160. [Abstract] [Full Text] [PDF]

				K. K. Koh, J. Y. Ahn, S. H. Han, D. S. Kim, D. K. Jin, H. S. Kim, M.-S. Shin, T. H. Ahn, I. S. Choi, and E. K. Shin Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients J. Am. Coll. Cardiol., September 3, 2003; 42(5): 905 - 910. [Abstract] [Full Text] [PDF]

				T. Itoh, J. Kajikuri, T. Tada, Y. Suzuki, and Y. Mabuchi Angiotensin II-induced modulation of endothelium-dependent relaxation in rabbit mesenteric resistance arteries J. Physiol., May 1, 2003; 548(3): 893 - 906. [Abstract] [Full Text] [PDF]

				B. Hornig, C. Kohler, D. Schlink, H. Tatge, and H. Drexler AT1-Receptor Antagonism Improves Endothelial Function in Coronary Artery Disease by a Bradykinin/B2-Receptor-Dependent Mechanism Hypertension, May 1, 2003; 41(5): 1092 - 1095. [Abstract] [Full Text] [PDF]

				T. Matsumoto, K. Minai, H. Horie, N. Ohira, H. Takashima, Y. Tarutani, Y. o Yasuda, T. Ozawa, S. Matsuo, M. Kinoshita, et al. Angiotensin-converting enzyme inhibition but not angiotensin II type 1 receptor antagonism augments coronary release of tissue plasminogen activator in hypertensive patients J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1373 - 1379. [Abstract] [Full Text] [PDF]

				P. O. Bonetti, L. O. Lerman, and A. Lerman Endothelial Dysfunction: A Marker of Atherosclerotic Risk Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 168 - 175. [Abstract] [Full Text] [PDF]

				N. Werner and G. Nickenig AT1 receptors in atherosclerosis: biological effects including growth, angiogenesis, and apoptosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A9 - A13. [Abstract] [PDF]

				U. Rueckschloss, M. T. Quinn, J. Holtz, and H. Morawietz Dose-Dependent Regulation of NAD(P)H Oxidase Expression by Angiotensin II in Human Endothelial Cells: Protective Effect of Angiotensin II Type 1 Receptor Blockade in Patients With Coronary Artery Disease Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1845 - 1851. [Abstract] [Full Text] [PDF]

				J. P. J. Halcox, K. R. A. Nour, G. Zalos, R. Mincemoyer, M. A. Waclawiw, C. E. Rivera, G. Willie, S. Ellahham, and A. A. Quyyumi The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1232 - 1240. [Abstract] [Full Text] [PDF]

				A. R. Brasier, A. Recinos III, and M. S. Eledrisi Vascular Inflammation and the Renin-Angiotensin System Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1257 - 1266. [Abstract] [Full Text] [PDF]

				S. Wassmann, S. Hilgers, U. Laufs, M. Bohm, and G. Nickenig Angiotensin II Type 1 Receptor Antagonism Improves Hypercholesterolemia-Associated Endothelial Dysfunction Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1208 - 1212. [Abstract] [Full Text] [PDF]

				G. Nickenig and D. G. Harrison The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis: Part I: Oxidative Stress and Atherogenesis Circulation, January 22, 2002; 105(3): 393 - 396. [Full Text] [PDF]

				D. Li, H. Chen, and J. L. Mehta Angiotensin II via Activation of Type 1 Receptor Upregulates Expression of Endoglin in Human Coronary Artery Endothelial Cells Hypertension, November 1, 2001; 38(5): 1062 - 1067. [Abstract] [Full Text] [PDF]

				A. Prasad, J. P. J. Halcox, M. A. Waclawiw, and A. A. Quyyumi Angiotensin type 1 receptor antagonism reverses abnormal coronary vasomotion in atherosclerosis J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1089 - 1095. [Abstract] [Full Text] [PDF]

				E. A. Jaimes, C. Sweeney, and L. Raij Effects of the Reactive Oxygen Species Hydrogen Peroxide and Hypochlorite on Endothelial Nitric Oxide Production Hypertension, October 1, 2001; 38(4): 877 - 883. [Abstract] [Full Text] [PDF]

				M. M. E. D. van den Eijnden, J. J. Saris, R. J. A. de Bruin, E. de Wit, W. Sluiter, T. L. Reudelhuber, M. A. D. H. Schalekamp, F. H. M. Derkx, and A. H. J. Danser Prorenin Accumulation and Activation in Human Endothelial Cells : Importance of Mannose 6-Phosphate Receptors Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 911 - 916. [Abstract] [Full Text] [PDF]

				S. Wassmann, U. Laufs, A. T. Baumer, K. Muller, K. Ahlbory, W. Linz, G. Itter, R. Rosen, M. Bohm, and G. Nickenig HMG-CoA Reductase Inhibitors Improve Endothelial Dysfunction in Normocholesterolemic Hypertension via Reduced Production of Reactive Oxygen Species Hypertension, June 1, 2001; 37(6): 1450 - 1457. [Abstract] [Full Text] [PDF]

				T. Omland, W. Johnson, M. B. Gordon, and M. A. Creager Endothelial function during stimulation of renin-angiotensin system by low-sodium diet in humans Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2248 - H2254. [Abstract] [Full Text] [PDF]

				M.-S. Zhou, A. Adam, and L. Raij Review: Interaction among angiotensin II, nitric oxide and oxidative stress Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S59 - S63. [PDF]

				B. Hornig, U. Landmesser, C. Kohler, D. Ahlersmann, S. Spiekermann, A. Christoph, H. Tatge, and H. Drexler Comparative Effect of ACE Inhibition and Angiotensin II Type 1 Receptor Antagonism on Bioavailability of Nitric Oxide in Patients With Coronary Artery Disease : Role of Superoxide Dismutase Circulation, February 13, 2001; 103(6): 799 - 805. [Abstract] [Full Text] [PDF]

				Y. Higashi, M. Sanada, S. Sasaki, K. Nakagawa, C. Goto, H. Matsuura, K. Ohama, K. Chayama, and T. Oshima Effect of Estrogen Replacement Therapy on Endothelial Function in Peripheral Resistance Arteries in Normotensive and Hypertensive Postmenopausal Women Hypertension, February 1, 2001; 37(2): 651 - 657. [Abstract] [Full Text] [PDF]

				L. Raij Workshop: Hypertension and Cardiovascular Risk Factors : Role of the Angiotensin II-Nitric Oxide Interaction Hypertension, February 1, 2001; 37(2): 767 - 773. [Abstract] [Full Text] [PDF]

				M. Oelze, H. Mollnau, N. Hoffmann, A. Warnholtz, M. Bodenschatz, A. Smolenski, U. Walter, M. Skatchkov, T. Meinertz, and T. Munzel Vasodilator-Stimulated Phosphoprotein Serine 239 Phosphorylation as a Sensitive Monitor of Defective Nitric Oxide/cGMP Signaling and Endothelial Dysfunction Circ. Res., November 24, 2000; 87(11): 999 - 1005. [Abstract] [Full Text] [PDF]

				A. Prasad, S. Narayanan, S. Husain, F. Padder, M. Waclawiw, N. Epstein, and A. A. Quyyumi Insertion-Deletion Polymorphism of the ACE Gene Modulates Reversibility of Endothelial Dysfunction With ACE Inhibition Circulation, July 4, 2000; 102(1): 35 - 41. [Abstract] [Full Text] [PDF]