Circulation, Vol 89, 2035-2040, Copyright © 1994 by American Heart Association
JS Stamler, E Loh, MA Roddy, KE Currie and MA Creager
BACKGROUND: The endothelium synthesizes and releases a relaxing factor with
the physiochemical properties of nitric oxide (NO). However, the role of
endothelium-derived NO in the basal regulation of systemic and pulmonary
vascular resistance in humans is not known. Our primary objectives were to
determine the effects of inhibiting NO synthesis on blood pressure and
systemic vascular resistance and to establish the role of
endothelium-derived NO in the regulation of normoxic pulmonary vascular
tone. METHODS AND RESULTS: We studied the systemic and pulmonary
hemodynamic effects of NG-monomethyl-L-arginine (L-NMMA, 0.03 to 1.0
mg.kg-1.min-1 IV), an NO synthase inhibitor, in 11 healthy volunteers, aged
33 +/- 2 years. An arterial cannula and a pulmonary artery catheter were
placed in each subject to measure blood pressure, pulmonary artery
pressure, and pulmonary capillary wedge pressure. Cardiac output was
determined by the Fick technique, and systemic and pulmonary vascular
resistances were calculated. Serum NO levels (free and protein bound) were
measured by chemiluminescence in 5 subjects. Six of the subjects also
received phenylephrine (25 to 100 micrograms/min IV) to compare the cardiac
hemodynamic effects of L-NMMA with those of a direct-acting
vasoconstrictor. L-NMMA caused dose- dependent increases in both blood
pressure and systemic vascular resistance. At the highest dose of L-NMMA,
there was a 15.5 +/- 1.3% increase in mean blood pressure and a 63.4 +/-
8.2% increase in systemic vascular resistance (each P < .01). Pulmonary
vascular resistance increased 39.8 +/- 9.4% (P < .01), whereas mean
pulmonary artery pressure did not change. Administration of L-NMMA also
reduced cardiac output by 27.8 +/- 2.9% and stroke volume by 15.4 +/- 3.5%
(each P < .01). Serum NO levels decreased 65 +/- 10% from basal values
(P < .05), confirming inhibition of endogenous NO production.
Phenylephrine increased blood pressure to a level comparable to that
observed with L-NMMA. The decline in stroke volume was greater with L- NMMA
than with phenylephrine (P < .01). CONCLUSIONS: This study demonstrates
that basal release of endothelium-derived NO is directly involved in the
determination of systemic vascular resistance and, therefore, blood
pressure in healthy humans. In addition, NO regulates basal normoxic
pulmonary vascular tone. The complex hemodynamic effects of NO are
composite properties of its actions on systemic and pulmonary vascular
resistance and cardiac function.
ARTICLES
Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115.
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M. J. Joyner and N. M. Dietz Nitric oxide and vasodilation in human limbs J Appl Physiol, December 1, 1997; 83(6): 1785 - 1796. [Abstract] [Full Text] [PDF]
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B. Preckel, G. Kojda, W. Schlack, D. Ebel, K. Kottenberg, E. Noack, V. Thamer, E. Noack, and V. Thämer Inotropic Effects of Glyceryl Trinitrate and Spontaneous NO Donors in the Dog Heart Circulation, October 21, 1997; 96(8): 2675 - 2682. [Abstract] [Full Text]
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 P. Mathieu, M. Carrier, J. Dupuis, J. Ryan, and L. C. Pelletier L-Arginine Prevents Cyclosporin A-Induced Pulmonary Vascular Dysfunction Ann. Thorac. Surg., August 1, 1997; 64(2): 414 - 420. [Abstract] [Full Text]
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W. Steudel, F. Ichinose, P. L. Huang, W. E. Hurford, R. C. Jones, J. A. Bevan, M. C. Fishman, and W. M. Zapol Pulmonary Vasoconstriction and Hypertension in Mice With Targeted Disruption of the Endothelial Nitric Oxide Synthase (NOS 3) Gene Circ. Res., July 19, 1997; 81(1): 34 - 41. [Abstract] [Full Text]
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X. COMBES, M. MAZMANIAN, H. GOURLAIN, and P. HERVÉ Effect of 48 Hours of Nitric Oxide Inhalation on Pulmonary Vasoreactivity in Rats Am. J. Respir. Crit. Care Med., July 1, 1997; 156(2): 473 - 477. [Abstract] [Full Text]
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H. H. Ting, F. K. Timimi, E. A. Haley, M.-A. Roddy, P. Ganz, and M. A. Creager Vitamin C Improves Endothelium-Dependent Vasodilation in Forearm Resistance Vessels of Humans With Hypercholesterolemia Circulation, June 17, 1997; 95(12): 2617 - 2622. [Abstract] [Full Text]
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M. R. Adams, W. Jessup, D. Hailstones, and D. S. Celermajer L-Arginine Reduces Human Monocyte Adhesion to Vascular Endothelium and Endothelial Expression of Cell Adhesion Molecules Circulation, February 4, 1997; 95(3): 662 - 668. [Abstract] [Full Text]
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H. SCHÜTTE, K. MAYER, T. GESSLER, M. RÜHL, J. SCHLAUDRAFF, H. BURGER, W. SEEGER, and F. GRIMMINGER Nitric Oxide Biosynthesis in an Exotoxin-induced Septic Lung Model . Role of cNOS and Impact on Pulmonary Hemodynamics Am. J. Respir. Crit. Care Med., February 1, 1997; 157(2): 498 - 504. [Abstract] [Full Text]
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M. A. Creager, M.-A. Roddy, K. Boles, and J. S. Stamler N-Acetylcysteine Does Not Influence the Activity of Endothelium-Derived Relaxing Factor In Vivo Hypertension, February 1, 1997; 29(2): 668 - 672. [Abstract] [Full Text]
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J. L. Myers, J. J. Wizorek, A. K. Myers, E. Yankah, M. T. Pettit, P. C. Kouretas, H. J. Dalton, Y. Wang, and R. A. Hopkins Pulmonary Arterial Endothelial Dysfunction Potentiates Hypercapnic Vasoconstriction and Alters the Response to Inhaled Nitric Oxide Ann. Thorac. Surg., December 1, 1996; 62(6): 1677 - 1684. [Abstract] [Full Text]
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 E. G. Shesely, N. Maeda, H.-S. Kim, K. M. Desai, J. H. Krege, V. E. Laubach, P. A. Sherman, W. C. Sessa, and O. Smithies Elevated blood pressures in mice lacking endothelial nitric oxide synthase PNAS, November 12, 1996; 93(23): 13176 - 13181. [Abstract] [Full Text] [PDF]
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 R. F. Furchgott The Discovery of Endothelium-Derived Relaxing Factor and Its Importance in the Identification of Nitric Oxide JAMA, October 9, 1996; 276(14): 1186 - 1188. [Abstract] [PDF]
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P. Mohan, D. L. Brutsaert, W. J. Paulus, and S. U. Sys Myocardial Contractile Response to Nitric Oxide and cGMP Circulation, March 15, 1996; 93(6): 1223 - 1229. [Abstract] [Full Text]
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M. Kelm, M. Preik, D. J. Hafner, and B. E. Strauer Evidence for a Multifactorial Process Involved in the Impaired Flow Response to Nitric Oxide in Hypertensive Patients With Endothelial Dysfunction Hypertension, March 1, 1996; 27(3): 346 - 353. [Abstract] [Full Text]
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C. J. Cooper, M. J. Landzberg, T. J. Anderson, F. Charbonneau, M. A. Creager, P. Ganz, and A. P. Selwyn Role of Nitric Oxide in the Local Regulation of Pulmonary Vascular Resistance in Humans Circulation, January 15, 1996; 93(2): 266 - 271. [Abstract] [Full Text]
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C. E. Garcia, C. M. Kilcoyne, C. Cardillo, R. O. Cannon III, A. A. Quyyumi, and J. A. Panza Effect of Copper-Zinc Superoxide Dismutase on Endothelium-Dependent Vasodilation in Patients With Essential Hypertension Hypertension, December 1, 1995; 26(6): 863 - 868. [Abstract] [Full Text]
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J. M. Hare, E. Loh, M. A. Creager, and W. S. Colucci Nitric Oxide Inhibits the Positive Inotropic Response to ß-Adrenergic Stimulation in Humans With Left Ventricular Dysfunction Circulation, October 15, 1995; 92(8): 2198 - 2203. [Abstract] [Full Text]
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Y. Naka, N. C. Chowdhury, H. Liao, D. K. Roy, M. C. Oz, R. E. Michler, and D. J. Pinsky Enhanced Preservation of Orthotopically Transplanted Rat Lungs by Nitroglycerin but Not Hydralazine : Requirement for Graft Vascular Homeostasis Beyond Harvest Vasodilation Circ. Res., May 1, 1995; 76(5): 900 - 906. [Abstract] [Full Text]
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Y. Su, S. I. Zharikov, and E. R. Block Microtubule-active agents modify nitric oxide production in pulmonary artery endothelial cells Am J Physiol Lung Cell Mol Physiol, June 1, 2002; 282(6): L1183 - L1189. [Abstract] [Full Text] [PDF]
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