Role of Nitric Oxide in the Control of Mitochondrial Function

  • Paul R. Forfia
  • Thomas H. Hintze
  • Michael S. Wolin
  • Gabor Kaley
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 471)


Nitric oxide (NO) has been a focus of intense scientific investigation over the past years. A vast array of physiologic as well as pathophysiologic roles for NO have been described in pulmonary, immunologic, neuronal, gastrointestinal, and reproductive systems.21 Undoubtedly however, the preponderance of nitric oxide research has focused on the role of NO in the cardiovascular system, both in normal and pathophysiologic states. Nitric oxide is involved in the control of mean arterial blood pressure, vascular tone and regional blood flow in virtually all vascular beds.1,34 In addition, NO prevents platelet aggregation and is an inhibitor of vascular smooth muscle proliferation. Thus, NO is believed to contribute significantly to the maintenance of vascular homeostasis. Despite ample evidence in support of the action of NO on vascular smooth muscle and the local abluminal environment, the role of NO in the control of tissue oxygen consumption has received relatively little attention. Thus, this chapter will discuss the role of NO in the control of tissue respiration, as well as possible physiologic and pathophysiologic implications linking endogenous NO production and oxygen utilization in mammalian systems.


Nitric Oxide Septic Shock Cytochrome Oxidase Mitochondrial Respiration Myocardial Oxygen Consumption 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Bevan, JA, G Kaley, and GM Rubanyi. Flow dependent regulation of vascular function PP 163-177, Oxford University Press, 1995.Google Scholar
  2. 2.
    Brown, GC and CE Cooper. Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Letters 356:295–298, 1994.PubMedCrossRefGoogle Scholar
  3. 3.
    Brudwig, GW, TH Stevens, and SI Chan. Reactions of nitric oxide with cytochrome c oxidase. Biochemistry 19:5275–5285, 1980.CrossRefGoogle Scholar
  4. 4.
    Cox, CD, WJ Payne, and DV Dervartanian. Electron paramagnetic resonance studies on the nature on hemoproteins in nitrite and nitric oxide reduction. Biochemica. et Biophysica ACTA. 253:290–294, 1971.CrossRefGoogle Scholar
  5. 5.
    Drapier, JC and JB Hibbs, Jr. Murine cytotoxic activated macrophages inhibit aconitase in tumor cells; inhibition involves the iron-sulfur prosthetic group and is reversible. J. Clin. Invest. 78:790–797, 1986.PubMedCrossRefGoogle Scholar
  6. 6.
    Elkayam, U, J Amin, A Mehra, J Vasquez, L Weber, and SH Rahimtoola. A prospective, randomized double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 82:1954–1961, 1990.PubMedCrossRefGoogle Scholar
  7. 7.
    Farrar, JA, AJ Thomson, MR Cheesman, DM Dooley, and WG Zumft. A model of the copper centres of nitrous oxide reductase. FEBS 294(12): 11–15, 1991.CrossRefGoogle Scholar
  8. 8.
    Forfia, PR, X Zhang, F Ochoa, M Ochoa, X Xu, RD Bernstein, PB Sehgal, NR Ferreri, and TH Hintze. Relationship between plasma NOx and cardiac and vascular dysfunction after LPS induction in anesthetized dogs. Am. J. Physiol. 274 (Heart Circ. Physiol. 43):H193–H201, 1998.PubMedGoogle Scholar
  9. 9.
    Forfia, PR, X Zhang, D Knight, MS Wolin, and TH Hintze. The role of nitric oxide in the modulation of myocardial oxygen consumption in the non-human primate; an alternative mechanism of action for a calcium channel blocker. Submitted, 1998.Google Scholar
  10. 10.
    Giulivi, C. Functional implications of nitric oxide produced by mitochondria in mitochondrial metabolism. Biochem. J. 332:673–699, 1998.PubMedGoogle Scholar
  11. 11.
    Granger, DL, RR Taintor, JL Cook, and JB Hibbs, Jr. Injury of neoplastic cells by murine macrophages leads to inhibition of mitochondrial respiration. J. Clin. Invest. 65:357–370, 1980.PubMedCrossRefGoogle Scholar
  12. 12.
    Granger, DL and A Lehninger. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells. J. Cell Biol. 95:527–535, 1982.PubMedCrossRefGoogle Scholar
  13. 13.
    Hibbs, JB, Z Vavrin, and RR Taintor. L-arginine is reqired for expression of the activated macrophage effector molecule mechanism causing selective metabolic inhibition in target cells. J. Immunol. 138:550–565, 1987.PubMedGoogle Scholar
  14. 14.
    Jones, DP. Intracellular diffusion gradients of O2 and ATP. Am. J. Physiol. 250:C663–C675, 1986.PubMedGoogle Scholar
  15. 15.
    Kasting, JF Earth’s early atmosphere. Science 259:920–926, 1993.PubMedCrossRefGoogle Scholar
  16. 16.
    Kichuk, MR, N Seyedi, X Zhang, CC Marboe, RE Michler, LJ Addonizio, G Kaley, A Nasjletti, and TH Hintze. Regulation of nitric oxide production in human coronary microvessels and the contribution of local kinin formation. Circulatioin 94:44–51, 1996.CrossRefGoogle Scholar
  17. 17.
    Kiechle, FL and T Malinski. Nitric oxide; biochemistry, pathophysiology, and detection. Am J. Clin. Pathol. 100:567–575, 1993.PubMedGoogle Scholar
  18. 18.
    King, CE, MJ Melinyshyn, JD Mewburn, SE Curtis, MJ Winn, SM Cain, and CK Chapler. Canine hindlimb blood flow and O2 uptake after inhibition of EDRF/NO synthesis. J. Appl. Physiol. 76:1166–1171, 1994.PubMedGoogle Scholar
  19. 19.
    Knowles, RG and S Moncada. Nitric oxide as a signal in blood vessels. TIBS 17:399–402, 1992.PubMedGoogle Scholar
  20. 20.
    Malmstrom, BG and R Aasa. The nature of the Cua center in cytochrome oxidase. FEBS Letters 325:49–52, 1993.PubMedCrossRefGoogle Scholar
  21. 21.
    Moncada, S, MJ Palmer, and EA Higgs. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43:109–142, 1991.PubMedGoogle Scholar
  22. 22.
    Okada, S, Y Takehara, M Yabaki, T Yoshioka, T Yasuda, M Inoue, and K Utsumi. Nitric oxide, a physiological modulator of mitochondrial function. Physiol. Chem. Phys. and Med. N MR 28:69–82, 1996.Google Scholar
  23. 23.
    Packer, ML, PD Kessler, and WH Lee. Calcium channel blockade in the management of severe chronic heart failure: a bridge too far. Circulation, 75(suppl V):V56–V64, 1987.PubMedGoogle Scholar
  24. 24.
    Saraste, M and J Castresana. Cytochrome oxidase evolved by tinkering with denitrification enzymes. FEBS Letters 341:1–4, 1994.PubMedCrossRefGoogle Scholar
  25. 25.
    Schweizer, M and C Richter. Nitric oxide potently and reversibly deenergizes mitochondria at low oxygen tensions. Biochem. and Biophys. Res. Commun. 204(l):169–175, 1994.CrossRefGoogle Scholar
  26. 26.
    Scott, RA, WG Zumft, CL Coyle, and DM Dooley. Pseudomonas stutzeri N2O reductase contains Cua-type sites. Proc. Natl. Acad. Sci. USA. 86:4082–4086, 1989.PubMedCrossRefGoogle Scholar
  27. 27.
    Sharpe, DN, J Murphy, R Coxan, and SF Hannan. Enalipril in patients with chronic heart failure: a placebo controlled, randomized, double-blind study. Circulation 70:271, 1984.PubMedCrossRefGoogle Scholar
  28. 28.
    Shen, WQ, TH Hintze, and MS Wolin. Nitric oxide; an important signaling mechanism between vascular endothelium and parenchymal cells in the regulation of oxygen consumption. Circulation 92:1086–1095, 1995.CrossRefGoogle Scholar
  29. 29.
    Simonson, SG, K Welty-Wolf, Y-C Huang, JA Griebel, MS Caplan, PJ Fracica, and CA Piantadosi. Altered mitochondrial redox responses in gram negative septic shock in primates. Circulatory Shock 43:34–43, 1994.PubMedGoogle Scholar
  30. 30.
    Smith, CJ, D Sun, C Hoegler, BS Roth, X Zhang, G Zhao, X-B Xu, Y Kobari, K Pritchard Jr, WC Sessa, and TH Hintze. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ. Res. 78:58–64, 1996.PubMedCrossRefGoogle Scholar
  31. 31.
    Stuehr, DJ and C Nathan. Nitric oxide; a macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J. Exp. Med. 169:1543–1555, 1989.PubMedCrossRefGoogle Scholar
  32. 32.
    Takehara, Y, H Nakamara, Y Inai, M Yabuki, K Hamazaki, T Yoshioka, M Inoue, AA Horton, and K Utsumi. Oxygen dependent reversible inhibition of mitochondrial respiration by nitric oxide. Cell Structure and Function 21:251–258, 1996.PubMedCrossRefGoogle Scholar
  33. 33.
    Torres, J, V Darley-Usmar, and MT Wilson. Inhibition of cytochrome c oxidase in turnover by nitric oxide: mechanism and implications for control of respiration. Biochem. J. 312:169–173, 1995.PubMedGoogle Scholar
  34. 34.
    Ulmans, JG and R Levi. Nitric oxide in the regulation of blood flow and arterial pressure. Annu. Rev. Physiol. 57:771–790, 1995.CrossRefGoogle Scholar
  35. 35.
    Vaughn, MW, L Kuo, and JC Liao. Effective diffusion distance of nitric oxide in the microcirculation. Am. J. Physiol. 274:H1705–H1714, 1998.PubMedGoogle Scholar
  36. 36.
    Vollack, KU, J Xie, E Hartig, U Romling, and WG Zumft. Localization of denitrification genes in the chromosomal map of Pseudomonas aeruginosa. Microbiology 144(2):441–448, 1998.PubMedCrossRefGoogle Scholar
  37. 37.
    Xie, YW, W Shen, G Zhao, X Xu, MS Wolin, TH Hintze. Role of endothelium-derived nitric oxide in the modulation of canine myocardial mitochondrial respiration in vitro. Circ Res. 79:381–387, 1996.PubMedCrossRefGoogle Scholar
  38. 38.
    Yonetani, T, JE Erman, JS Leigh, and GH Reed. Electromagnetic properties of hemoproteins. J. of Biol. Chem. 247(8):2447–2455, 1972.Google Scholar
  39. 39.
    Zhang, X, YW Xie, A Nasjletti, X Xu, MS Wolin, and TH Hintze. ACE inhibitors promote nitric oxide accumulation to modulate myocardial oxygen consumption. Circulation 95:176–182, 1997.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Paul R. Forfia
    • 1
  • Thomas H. Hintze
    • 1
  • Michael S. Wolin
    • 1
  • Gabor Kaley
    • 1
  1. 1.Department of PhysiologyNew York Medical CollegeValhallaUSA

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