© 1997 American Heart Association, Inc.
Articles |
Reduced Responsiveness of Hypercholesterolemic Rabbit Aortic Smooth Muscle Cells to Nitric Oxide
the Vascular Biology Unit, Robert Dawson Evans Department of Clinical Research, Department of Medicine, Boston (Mass) University Medical Center.
Correspondence to Richard A. Cohen, MD, Vascular Biology Unit, R408, Boston University Medical Center, 80 E Concord St, Boston, MA 02118. E-mail racohen@med-med1.bu.edu.
The response to nitric oxide of intracellular free Ca2+ levels, measured by fura 2 fluorimetry, and cyclic GMP, measured by RIA, was evaluated on smooth muscle cells of the thoracic aorta in primary culture from normal and cholesterol-fed rabbits. Relaxation to acetylcholine and nitric oxide was also determined in isolated rings of aorta. After 10 weeks of high-cholesterol diet, the intact aorta relaxed less to both acetylcholine and nitric oxide. In cultured cells from hypercholesterolemic rabbits, intracellular Ca2+ oscillated, and the mean Ca2+ levels were approximately twofold greater than in normal aortic cells. Nitric oxide failed to affect basal Ca2+ in either cell type. The peak and sustained rise in intracellular Ca2+ induced by angiotensin II (10-7 mol/L) were similar in the two cell types. However, nitric oxide (10-10 to 10-6 mol/L) decreased the sustained Ca2+ levels to a significantly smaller extent in cells from cholesterol-fed rabbits. In addition, in cells from hypercholesterolemic rabbits, nitric oxide added before angiotensin II inhibited to a smaller degree the transient increase in intracellular free Ca2+ caused by angiotensin II in the nominal absence of extracellular Ca2+, as well as the increase in Ca2+ associated with the addition of extracellular Ca2+. Measurements of fura 2 quenching caused by Mn2+ influx confirmed that nitric oxide inhibited the entry of extracellular divalent cations significantly less in cells from hypercholesterolemic rabbits. Basal levels of cyclic GMP were significantly less than normal, and nitric oxide increased levels of cyclic GMP to a significantly smaller degree in cells from cholesterol-fed rabbits. These data indicate a substantial resistance to nitric oxide action in aortic smooth muscle cells of cholesterol-fed rabbits. This observation is consistent with the notion that resistance of smooth muscle cells to nitric oxide contributes to abnormal endothelium-dependent vasodilatation during hypercholesterolemia and can play a role in the pathogenesis of atherosclerosis.
Key Words: nitric oxide • calcium • cyclic GMP • cholesterol • atherosclerosis • smooth muscle cell
This article has been cited by other articles:
 |
|
 |
|
  E. A. Mokelke, Q. Hu, M. Song, L. Toro, H. K. Reddy, and M. Sturek Altered functional coupling of coronary K+ channels in diabetic dyslipidemic pigs is prevented by exercise J Appl Physiol, September 1, 2003; 95(3): 1179 - 1193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Jackson and F. Giuliano Moderators' introduction Eur. Heart J. Suppl., December 1, 2002; 4(suppl_H): H1 - H6. [Abstract] [PDF]
|
|
|
|
 |
|
 T. Adachi, R. Matsui, S. Xu, M. Kirber, H. L. Lazar, V. S. Sharov, C. Schoneich, and R. A. Cohen Antioxidant Improves Smooth Muscle Sarco/Endoplasmic Reticulum Ca2+-ATPase Function and Lowers Tyrosine Nitration in Hypercholesterolemia and Improves Nitric Oxide-Induced Relaxation Circ. Res., May 31, 2002; 90(10): 1114 - 1121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Itoh, S. Umemoto, M. Hiromoto, Y. Toma, Y. Tomochika, S. Aoyagi, M. Tanaka, T. Fujii, and M. Matsuzaki Importance of NAD(P)H Oxidase-Mediated Oxidative Stress and Contractile Type Smooth Muscle Myosin Heavy Chain SM2 at the Early Stage of Atherosclerosis Circulation, May 14, 2002; 105(19): 2288 - 2295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gonzalez-Santiago, S. Lopez-Ongil, M. Rodriguez-Puyol, and D. Rodriguez-Puyol Decreased Nitric Oxide Synthesis in Human Endothelial Cells Cultured on Type I Collagen Circ. Res., March 22, 2002; 90(5): 539 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Adachi, R. Matsui, R. M. Weisbrod, S. Najibi, and R. A. Cohen Reduced Sarco/Endoplasmic Reticulum Ca2+ Uptake Activity Can Account for the Reduced Response to NO, but Not Sodium Nitroprusside, in Hypercholesterolemic Rabbit Aorta Circulation, August 28, 2001; 104(9): 1040 - 1045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. V. d'Uscio, T. A. Baker, C. B. Mantilla, L. Smith, D. Weiler, G. C. Sieck, and Z. S. Katusic Mechanism of Endothelial Dysfunction in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 1017 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Didion, D. D. Heistad, and F. M. Faraci Mechanisms That Produce Nitric Oxide-Mediated Relaxation of Cerebral Arteries During Atherosclerosis Stroke, March 1, 2001; 32(3): 761 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Sherman, J. F. Keaney Jr, E. S. Biegelsen, S. J. Duffy, J. D. Coffman, and J. A. Vita Pharmacological Concentrations of Ascorbic Acid Are Required for the Beneficial Effect on Endothelial Vasomotor Function in Hypertension Hypertension, April 1, 2000; 35(4): 936 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Feldstein, J. D. Krier, M. H. Sarafov, A. Lerman, P. J. M. Best, S. H. Wilson, and L. O. Lerman In Vivo Renal Vascular and Tubular Function in Experimental Hypercholesterolemia Hypertension, October 1, 1999; 34(4): 859 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. KEANEY JR., D. I. SIMON, and J. E. FREEDMAN Vitamin E and vascular homeostasis: implications for atherosclerosis FASEB J, June 1, 1999; 13(9): 965 - 975. [Abstract] [Full Text]
|
|
|
|
|
|
R. A. Cohen, R. M. Weisbrod, M. Gericke, M. Yaghoubi, C. Bierl, and V. M. Bolotina Mechanism of Nitric Oxide–Induced Vasodilatation : Refilling of Intracellular Stores by Sarcoplasmic Reticulum Ca2+ ATPase and Inhibition of Store-Operated Ca2+ Influx Circ. Res., February 5, 1999; 84(2): 210 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Miller, D. D. Gutterman, C. D. Rios, D. D. Heistad, and B. L. Davidson Superoxide Production in Vascular Smooth Muscle Contributes to Oxidative Stress and Impaired Relaxation in Atherosclerosis Circ. Res., June 29, 1998; 82(12): 1298 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gonzalez-Santiago, S. Lopez-Ongil, M. Rodriguez-Puyol, and D. Rodriguez-Puyol Decreased Nitric Oxide Synthesis in Human Endothelial Cells Cultured on Type I Collagen Circ. Res., March 22, 2002; 90(5): 539 - 545. [Abstract] [Full Text] [PDF]
|
|