Arteriosclerosis and Thrombosis, Vol 14, 753-759, Copyright © 1994 by American Heart Association

ARTICLES

Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits

AJ Cayatte, JJ Palacino, K Horten and RA Cohen
Robert Dawson Evans Department of Clinical Research, Boston University School of Medicine, Mass. 02118.

To determine if endogenous local levels of nitric oxide (NO) modulate atherogenesis, we studied the effect of inhibiting NO with NG-nitro-L- arginine methyl ester (L-NAME) on early neointima formation in cholesterol-fed rabbits. Male rabbits were fed for 5 weeks with a 0.5% cholesterol diet alone or treated in addition during the last 4 weeks with L-NAME (12 mg/kg per day SC) via osmotic minipump. Endothelial cell function was assessed in isolated aortic rings by vascular reactivity and levels of cyclic GMP. In L-NAME-treated rabbits there was inhibition of endothelium-dependent relaxations to acetylcholine and the calcium ionophore A23187 as well as impaired cyclic GMP accumulation in response to acetylcholine. Neointima formation in the ascending thoracic aorta was assessed by determining media and intima cross-sectional areas with computerized image analysis. Compared with rabbits that consumed the cholesterol diet alone, L-NAME-treated rabbits had significant increases in lesion area (0.29 +/- 0.04 versus 0.15 +/- 0.03 mm2) and in lesion/media ratio (0.06 +/- 0.01 versus 0.03 +/- 0.01). Plasma levels of cholesterol and fluorescent lipid peroxide products were unchanged, suggesting no difference in cholesterol metabolism or oxidation. Because arterial blood pressure was not altered by L-NAME treatment, the increased atherogenesis could not be attributed to an increase in blood pressure. These results indicated that local inhibition of NO accelerates early neointima formation possibly because of modulating monocyte recruitment or foam cell lipid accumulation.

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				H. Qian, V. Neplioueva, G. A. Shetty, K. M. Channon, and S. E. George Nitric Oxide Synthase Gene Therapy Rapidly Reduces Adhesion Molecule Expression and Inflammatory Cell Infiltration in Carotid Arteries of Cholesterol-Fed Rabbits Circulation, June 15, 1999; 99(23): 2979 - 2982. [Abstract] [Full Text] [PDF]

				J. P Cooke The 1998 Nobel prize in Medicine: clinical implications for 1999 and beyond Vascular Medicine, May 1, 1999; 4(2): 57 - 60. [PDF]

				C. A. D. Nascimento, K. Kauser, and G. M. Rubanyi Effect of 17beta -estradiol in hypercholesterolemic rabbits with severe endothelial dysfunction Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1788 - H1794. [Abstract] [Full Text] [PDF]

				H. Miyazaki, H. Matsuoka, J. P. Cooke, M. Usui, S. Ueda, S. Okuda, and T. Imaizumi Endogenous Nitric Oxide Synthase Inhibitor : A Novel Marker of Atherosclerosis Circulation, March 9, 1999; 99(9): 1141 - 1146. [Abstract] [Full Text] [PDF]

				T. Le Tourneau, E. Van Belle, D. Corseaux, B. Vallet, G. Lebuffe, B. Dupuis, J.-M. Lablanche, E. McFadden, C. Bauters, and M. E. Bertrand Role of nitric oxide in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling J. Am. Coll. Cardiol., March 1, 1999; 33(3): 876 - 882. [Abstract] [Full Text] [PDF]

				J. M. Bosmans, C. J. Vrints, M. M. Kockx, H. Bult, K. M. C. Cromheeke, and A. G. Herman Continuous Perivascular L-Arginine Delivery Increases Total Vessel Area and Reduces Neointimal Thickening After Experimental Balloon Dilatation Arterioscler. Thromb. Vasc. Biol., March 1, 1999; 19(3): 767 - 776. [Abstract] [Full Text] [PDF]

				J. T. KIELSTEIN, R. H. BÖGER, S. M. BODE-BÖGER, J. SCHÄFFER, M. BARBEY, K. M. KOCH, and J. C. FRÖLICH Asymmetric Dimethylarginine Plasma Concentrations Differ in Patients with End-Stage Renal Disease: Relationship to Treatment Method andAtherosclerotic Disease J. Am. Soc. Nephrol., March 1, 1999; 10(3): 594 - 600. [Abstract] [Full Text]

				C. Depre, X. Havaux, J. Renkin, J. L. J. Vanoverschelde, and W. Wijns Expression of inducible nitric oxide synthase in human coronary atherosclerotic plaque Cardiovasc Res, February 1, 1999; 41(2): 465 - 472. [Abstract] [Full Text] [PDF]

				K. P. Makaritsis, H. Gavras, Y. Du, A. V. Chobanian, and P. Brecher {alpha}1-Adrenergic Plus Angiotensin Receptor Blockade Reduces Atherosclerosis in Apolipoprotein E–Deficient Mice Hypertension, December 1, 1998; 32(6): 1044 - 1048. [Abstract] [Full Text] [PDF]

				M. Barton, C. C. Haudenschild, L. V. d'Uscio, S. Shaw, K. Munter, and T. F. Luscher Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice PNAS, November 24, 1998; 95(24): 14367 - 14372. [Abstract] [Full Text] [PDF]

				R. H. Boger, S. M. Bode-Boger, A. Szuba, P. S. Tsao, J. R. Chan, O. Tangphao, T. F. Blaschke, and J. P. Cooke Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction : Its Role in Hypercholesterolemia Circulation, November 3, 1998; 98(18): 1842 - 1847. [Abstract] [Full Text] [PDF]

				K. Hibi, T. Ishigami, K. Tamura, S. Mizushima, N. Nyui, T. Fujita, H. Ochiai, M. Kosuge, Y. Watanabe, Y. Yoshii, et al. Endothelial Nitric Oxide Synthase Gene Polymorphism and Acute Myocardial Infarction Hypertension, September 1, 1998; 32(3): 521 - 526. [Abstract] [Full Text] [PDF]

				M. Usui, T. Ichiki, M. Katoh, K. Egashira, and A. Takeshita Regulation of Angiotensin II Receptor Expression by Nitric Oxide in Rat Adrenal Gland Hypertension, September 1, 1998; 32(3): 527 - 533. [Abstract] [Full Text] [PDF]

				J. Vasquez-Vivar, B. Kalyanaraman, P. Martasek, N. Hogg, B. S. S. Masters, H. Karoui, P. Tordo, and K. A. Pritchard Jr. Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors PNAS, August 4, 1998; 95(16): 9220 - 9225. [Abstract] [Full Text] [PDF]

				J. K. Liao Endothelium and acute coronary syndromes Clin. Chem., August 1, 1998; 44(8): 1799 - 1808. [Abstract] [Full Text] [PDF]

				R. Scalia, J. Z. Appel III, and A. M. Lefer Leukocyte-Endothelium Interaction During the Early Stages of Hypercholesterolemia in the Rabbit : Role of P-Selectin, ICAM-1, and VCAM-1 Arterioscler. Thromb. Vasc. Biol., July 1, 1998; 18(7): 1093 - 1100. [Abstract] [Full Text] [PDF]

				S. Ravalli, A. Albala, M. Ming, M. Szabolcs, A. Barbone, R. E. Michler, and P. J. Cannon Inducible Nitric Oxide Synthase Expression in Smooth Muscle Cells and Macrophages of Human Transplant Coronary Artery Disease Circulation, June 16, 1998; 97(23): 2338 - 2345. [Abstract] [Full Text] [PDF]

				P. R. Myers and M. A. Tanner Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen : Role of Nitric Oxide Arterioscler. Thromb. Vasc. Biol., May 1, 1998; 18(5): 717 - 722. [Abstract] [Full Text] [PDF]

				R. A. Vogel and M. C. Corretti Estrogens, Progestins, and Heart Disease : Can Endothelial Function Divine the Benefit? Circulation, April 7, 1998; 97(13): 1223 - 1226. [Full Text] [PDF]