Heart Failure Reviews

, Volume 8, Issue 1, pp 35–46 | Cite as

Role of Nitric Oxide in the Pathophysiology of Heart Failure

  • Hunter C. Champion
  • Michel W. Skaf
  • Joshua M. Hare


Nitric oxide (NO) plays critical roles in the regulation of integrated cardiac and vascular function and homeostasis. An understanding of the physiologic role and relative contribution of the three NO synthase isoforms (neuronal—NOS1, inducible—NOS2, and endothelial—NOS3) is imperative to comprehend derangements of the NO signaling pathway in the failing cardiovascular system. Several theories of NO and its regulation have developed as explanations for the divergent observations from studies in health and disease states. Here we review the physiologic and pathophysiologic influence of NO on cardiac function, in a framework that considers several theories of altered NO signaling in heart failure. We discuss the notion of spatial compartmentalization of NO signaling within the myocyte in an effort to reconcile many controversies about derangements in the influences of NO in the heart and vasculature.

nitric oxide heart failure spatial compartmentalization myocyte 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Stamler JS, Lamas S, Fang FC. Nitrosylation. The prototypic redox-based signaling mechanism. Cell 2001;106:675-683.Google Scholar
  2. 2.
    Hare JM, Stamler JS. NOS: Modulator, not mediator of cardiac performance. Nat Med 1999;5:273-274.Google Scholar
  3. 3.
    Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O'Rourke B, Rodriguez ER, Huang PL, Lima J A, Berkowitz DE, Hare JM. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 2002;416:337-339.Google Scholar
  4. 4.
    Michel T, Feron O. Nitric oxide synthases: Which, where, how and why? J Clin Invest 1997;100:2146-2152.Google Scholar
  5. 5.
    Bates TE, Loesch A, Burnstock G, Clark JB. Mitochondrial nitric oxide synthase: A ubiquitous regulator of oxidative phosphorylation? Biochem Biophys Res Comm 1996;218:40-44.Google Scholar
  6. 6.
    XuKY, Huso DL, Dawson T, BredtDS, BeckerLC.NOsynthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci USA 1999;96:657-662.Google Scholar
  7. 7.
    Rosas GO, Zieman SJ, Donabedian M, Vandegaer K, Hare JM. Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma. JMol Cell Cardiol 2001;33:1849-1859.Google Scholar
  8. 8.
    Funakoshi H, Kubota T, Kawamura N, Machida Y, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A. Disruption of inducible nitric oxide synthase improves betaadrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy. Circ Res 2002;90:959-965.Google Scholar
  9. 9.
    Hare JM, Givertz MM, Creager MA, Colucci WS. Increased sensitivity to nitric oxide synthase inhibition in patients with heart failure: Potentiation of ?-adrenergic inotropic responsiveness. Circulation 1998;97:161-166.Google Scholar
  10. 10.
    Recchia FA, McConnell PI, Bernstein RD, Vogel TR, Xu X, Hintze TH. Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog. Circ Res 1998;83:969-979.Google Scholar
  11. 11.
    Saavedra WF, Paolocci N, St John ME, Skaf MW, Stewart GC, Xie JS, Harrison RW, Zeichner J, Mudrick D, Marban E, Kass DA, Hare JM. Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. Circ Res 2002;90:297-304.Google Scholar
  12. 12.
    Xu L, Eu JP, Meissner G, Stamler JS. Activation of the cardiac calcium release channel (Ryanodine receptor) by Poly-S-Nitrosylation. Science 1998;279:234-237.Google Scholar
  13. 13.
    Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium. Br J Pharmacol 1992;105:575-580.Google Scholar
  14. 14.
    Balligand J-L, Ungureanu-Longrois D, Simmons WW, Pimental D, Malinski TA, Kapturczak M, Taha Z, Lowenstein CJ, Davidoff AJ, Kelly RA, Smith TW, Michel T. Cytokine-inducible nitric-oxide synthase (iNOS) expression in cardiac myocytes: Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem 1994;269:27580-27588.Google Scholar
  15. 15.
    Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201-1206.Google Scholar
  16. 16.
    Torre-Amione G, Kapadia S, Lee J, Durand J-B, Bies RD, Young JB, Mann DL. Tumor necrosis factor-? and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704-711.Google Scholar
  17. 17.
    Heger J, Godecke A, Flogel U, Merx MW, Molojavyi A, Kuhn-Velten WN, Schrader J. Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. Circ Res 2002;90:93-99.Google Scholar
  18. 18.
    Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 2000;87:241-247.Google Scholar
  19. 19.
    Shindo T, Ikeda U, Ohkawa F, Kawahara Y, Yokoyama M, Shimada K. Nitric oxide synthesis in cardiac myocytes and fibroblasts by inflammatory cytokines. Cardiovasc Res 1995;29:813-819.Google Scholar
  20. 20.
    Pinsky DJ, Cai B, Yang X, Rodriguez C, Sciacca RR, Cannon PJ. The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor ?. J Clin Invest 1995;95:677-685.Google Scholar
  21. 21.
    Ferdinandy P, Panas D, Schulz R. Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts. Am J Physiol 1999;276:H1861-H1867.Google Scholar
  22. 22.
    Oyama J, Shimokawa H, Momii H, Cheng X, Fukuyama N, Arai Y, Egashira K, Nakazawa H, Takeshita A. Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardial dysfunction in dogs in vivo. J Clin Invest 1998;101:2207-2214.Google Scholar
  23. 23.
    Xie Y-W, Kaminski PM, Wolin MS. Inhibition of rat cardiac muscle contraction and mitochondrial respiration by endogenous peroxynitrite formation during posthypoxic reoxygenation. Circ Res 1998;82:891-897.Google Scholar
  24. 24.
    Szabo C, Ferrer-Sueta G, Zingarelli B, Southan GJ, Salzman AL, Radi R. Mercaptoethylguanidine and guanidine inhibitors of nitric-oxide synthase react with peroxynitrite and protect against peroxynitrite-induced oxidative damage. J Biol Chem 1997;272:9030-9036.Google Scholar
  25. 25.
    Lopez BL, Liu GL, Christopher TA, Ma X. Peroxynitrite, the product of nitric oxide and superoxide, causes myocardial injury in the isolated perfused rat heart. Coronary Artery Disease 1997;8:149-153.Google Scholar
  26. 26.
    Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 1997;100:2153- 2157.Google Scholar
  27. 27.
    Ito K, Akita H, Kanazawa K, Yamada S, Terashima M, Matsuda Y, Yokoyama M. Comparison of effects of ascorbic acid on endothelium-dependent vasodilation in patients with chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy versus patients with effort angina pectoris secondary to coronary artery disease. Am J Cardiol 1998;82:762-767.Google Scholar
  28. 28.
    Smith CJ, Sun D, Hoegler C, Roth BS, Zhang X, Zhao G, Xu XB, Kobari Y, Pritchard KJ, Sessa WC, Hintze TH. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ Res 1996;78:58-64.Google Scholar
  29. 29.
    Stein B, Eschenhagen T, Rudiger J, Scholz H, Forstermann U, Gath I. Increased expression of constitutive nitric oxide synthase III, but not inducible nitric oxide synthase II, in human heart failure. J Am Coll Cardiol 1998;32:1179-1186.Google Scholar
  30. 30.
    Fukuchi M, Hussain SN, Giaid A. Heterogeneous expression and activity of endothelial and inducible nitric oxide synthases in end-stage human heart failure: Their relation to lesion site and beta-adrenergic receptor therapy. Circulation 1998;98:132-139.Google Scholar
  31. 31.
    Werner ER, Werner-Felmayer G, Mayer B. Tetrahydrobiopterin, cytokines, and nitric oxide synthesis. Proc Soc Exp Biol Med 1998;219:171-182.Google Scholar
  32. 32.
    Shimizu S, Ishii M, Momose K, Yamamoto T. Role of tetrahydrobiopterin in the function of nitric oxide synthase, and its cytoprotective effect (Review). Int J Mol Med 1998;2:533-540.Google Scholar
  33. 33.
    Cooke JP, Dzau VJ. Derangements of the nitric oxide synthase pathway, L-arginine, and cardiovascular diseases. Circulation 1997;96:379-382.Google Scholar
  34. 34.
    Zieman SJ, Gerstenblith G, Lakatta EG, Rosas GO, Vandegaer K, Ricker KM, Hare JM. Upregulation of the nitric oxide-cGMP pathway in aged myocardium: Physiological response to L-arginine. Circ Res 2001;88:97-102.Google Scholar
  35. 35.
    McNamara DB, Bedi B, Aurora H, Tena L, Ignarro LJ, Kadowitz PJ, Akers DL. L-arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem Biophys Res Commun 1993;193:291-296.Google Scholar
  36. 36.
    Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ, Champion HC. Increased expression of arginase II in human diabetic corpus cavernosum: In diabetic-associated erectile dysfunction. Biochem Biophys Res Commun 2001;283:923-927.Google Scholar
  37. 37.
    Balligand JL, Cannon PJ. Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences. Arterioscler Thromb Vasc Biol 1997;17:1846-1858.Google Scholar
  38. 38.
    Shah AM, MacCarthy PA. Paracrine and autocrine effects of nitric oxide on myocardial function. Pharmacol Ther 2000;86:49-86.Google Scholar
  39. 39.
    Campbell DL, Stamler JS, Strauss HC. Redox modulation of L-type calcium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols. J Gen Physiol 1996;108:277-293.Google Scholar
  40. 40.
    Sun J, Xin C, Eu JP, Stamler JS, Meissner G. Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO. Proc Natl Acad Sci USA 2001;98:11158-11162.Google Scholar
  41. 41.
    Clementi E, Brown GC, Feelisch M, Moncada S. Persistent inhibition of cell respiration by nitric oxide: Crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc Natl Acad Sci USA 1998;95:7631-7636.Google Scholar
  42. 42.
    Gross WL, Bak MI, Ingwall JS, Arstall MA, Smith TW, Balligand J-L, Kelly RA. Nitric oxide inhibits creatine kinase and regulates rat heart contractile reserve. Proc Natl Acad Sci USA 1996;93:5604-5609.Google Scholar
  43. 43.
    Moro MA, Darley-Usmar VM, Lizasoain I, Su Y, Knowles RG, Radomski MW, Moncada S. The formation of nitric oxide donors from peroxynitrite. Br J Pharmacol 1995;116:1999-2004.Google Scholar
  44. 44.
    Wu M, Pritchard KA Jr, Kaminski PM, Fayngersh RP, Hintze TH, Wolin MS. Involvement of nitric oxide and nitrosothiols in relaxation of pulmonary arteries to peroxynitrite. Am J Physiol 1994;266:H2108-H2113.Google Scholar
  45. 45.
    Gow AJ, Chen Q, Hess DT, Day BJ, Ischiropoulos H, Stamler JS. Basal and stimulated protein S-nitrosylation in multiple cell types and tissues. J Biol Chem 2002;277:9637-9640.Google Scholar
  46. 46.
    Hess DT, Matsumoto A, Nudelman R, Stamler JS. Snitrosylation: Spectrum and specificity. Nat Cell Biol 2001;3:E46-E49.Google Scholar
  47. 47.
    Brady AJB, Poole-Wilson PA, Harding SE, Warren JB. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992;263:H1963-H1966.Google Scholar
  48. 48.
    Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Assessment by bicoronary sodium nitroprusside infusion. Circulation 1994;89: 2070-2078.Google Scholar
  49. 49.
    Mohan P, Brutsaert DL, Paulus WJ. Myocardial contractile response to nitric oxide and cGMP. Circulation 1996;93:1223-1229.Google Scholar
  50. 50.
    Kojda G, Kottenberg K, Noack E. Inhibition of nitric oxide synthase and soluble guanylate cyclase induces cardiodepressive effects in normal rat hearts. Eur J Pharmacol 1997;334:181-190.Google Scholar
  51. 51.
    Kojda G, Kottenberg K. Regulation of basal myocardial function by NO. Cardiovasc Res 1999;41:514-523.Google Scholar
  52. 52.
    Cotton JM, Kearney MT, MacCarthy PA, Grocott-Mason RM, McClean DR, Heymes C, Richardson PJ, Shah AM. Effects of nitric oxide synthase inhibition on basal function and the force-frequency relationship in the normal and failing human heart in vivo. Circulation 2001;104:2318-2323.Google Scholar
  53. 53.
    Hare JM, Lofthouse RA, Juang GJ, Colman L, Ricker KM, Kim B, Senzaki H, Cao S, Tunin RS, Kass DA. Contribution of caveolin protein abundance to augmented nitric oxide signaling in conscious dogs with pacing-induced heart failure. Circ Res 2000;86:1085-1092.Google Scholar
  54. 54.
    Harrison RW, Thakkar RN, Senzaki H, Ekelund UE, Cho E, Kass DA, Hare JM. Relative contribution of preload and afterload to the reduction in cardiac output caused by nitric oxide synthase inhibition with L-N(G)-methylarginine hydrochloride 546C88. Crit Care Med 2000;28:1263-1268.Google Scholar
  55. 55.
    Gyurko R, Kuhlencordt P, Fishman MC, Huang PL. Modulation of mouse cardiac function in vivo by eNOS and ANP. Am J Physiol Heart Circ Physiol 2000;278:H971- H981.Google Scholar
  56. 56.
    Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995;377:239-242.Google Scholar
  57. 57.
    Abi-Gerges N, Fischmeister R, Mery PF. G proteinmediated inhibitory effect of a nitric oxide donor on the L-type Ca2+ current in rat ventricular myocytes. J Physiol (Lond) 2001;531:117-130.Google Scholar
  58. 58.
    Gallo MP, Malan D, Bedendi I, Biasin C, Alloatti G, Levi RC. Regulation of cardiac calcium current by NO and cGMP-modulating agents. Pflugers Arch 2001;441:621-628.Google Scholar
  59. 59.
    Bartunek J, Shah AM, Vanderheyden M, Paulus WJ. Dobutamine enhances cardiodepressant effects of receptor-mediated coronary endothelial stimulation. Circulation 1997;95:90-96.Google Scholar
  60. 60.
    Heymes C, Vanderheyden M, Bronzwaer JG, Shah AM, Paulus WJ. Endomyocardial nitric oxide synthase and left ventricular preload reserve in dilated cardiomyopathy. Circulation 1999;99:3009-3016.Google Scholar
  61. 61.
    Flesch M, Kilter H, Cremers B, Lenz O, Sudkamp M, Kuhn-Regnier F, Bohm M. Acute effects of nitric oxide and cyclicGMPon human myocardial contractility. J Pharmacol Exp Ther 1997;281:1340-1349.Google Scholar
  62. 62.
    Smith JA, Shah AM, Lewis MJ. Factors released from endocardium of the ferret and pig modulate myocardial contraction. J Physiol 1991;439:1-14.Google Scholar
  63. 63.
    Grocott-Mason R, Anning P, Evans H, Lewis M, Shah A. Modulation of left ventricular relaxation in isolated ejecting heart by endogenous nitric oxide. Am J Physiol 1994;267:H1804-H1813.Google Scholar
  64. 64.
    Anning PB, Grocott-Mason RM, Lewis MJ, Shah AM. Enhancement of left ventricular relaxation in the isolated heart by an angiotensin-converting enzyme inhibitor. Circulation 1995;92:2660-2665.Google Scholar
  65. 65.
    Shah AM, Lewis MJ, Henderson AH. Effects of 8-bromocyclic GMP on contraction and on inotropic response of ferret cardiac muscle. J Mol Cell Cardiol 1991;23:55-64.Google Scholar
  66. 66.
    Shah AM, Spurgeon HA, Sollott SJ, Talo A, Lakatta EG. 8-bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. Circ Res 1994;74:970-978.Google Scholar
  67. 67.
    Shah AM. Paracrine modulation of heart cell function by endothelial cells. Cardiovasc Res 1996;31:847-867.Google Scholar
  68. 68.
    Vila-Petroff MG, Younes A, Egan J, Lakatta EG, Sollott SJ. Activation of distinct cAMP-dependent and cGMPdependent pathways by nitric oxide in cardiac myocytes. Circ Res 1999;84:1020-1031.Google Scholar
  69. 69.
    Paulus WJ, Vantrimpont PJ, Shah AM. Paracrine coronary endothelial control of left ventricular function in humans. Circulation 1995;92:2119-2126.Google Scholar
  70. 70.
    Dzimiri N. Regulation of beta-adrenoceptor signaling in cardiac function and disease. Pharmacol Rev 1999;51:465-501.Google Scholar
  71. 71.
    Hartzell HC, Fischmeister R. Opposite effects of cyclic GMPand cyclicAMPon Ca2+ current in single heart cells. Nature 1986;323:273-275.Google Scholar
  72. 72.
    Henning RJ, Khalil IR, Levy MN.Vagal stimulation attenuates sympathetic enhancement of left ventricular function. Am J Physiol 1990;258:H1470-H1475.Google Scholar
  73. 73.
    Hare JM, Kim B, Flavahan NA, Ricker KM, Peng X, Colman L, Weiss RG, Kass DA. Pertussis toxin-sensitive G proteins influence nitric oxide synthase III activity and protein levels in rat heart. J Clin Invest 1998;101:1424- 1431.Google Scholar
  74. 74.
    Hare JM, Keaney JF Jr, Balligand JL, Loscalzo J, Smith TW, Colucci WS. Role of nitric oxide in parasympathetic modulation of beta-adrenergic myocardial contractility in normal dogs. J Clin Invest 1995;95(1):360-366.Google Scholar
  75. 75.
    Mery P-F, Lohmann SM, Walter U, Fischmeister R. Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes. Proc Natl Acad Sci USA 1991;88:1197-1201.Google Scholar
  76. 76.
    Mery P-F, Pavoine C, Belhassen L, Pecker F, Fischmeister R. Nitric oxide regulates cardiac Ca2+ current. Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activity. J Biol Chem 1993;268:26286-26295.Google Scholar
  77. 77.
    Ji GJ, Fleischmann BK, Bloch W, Feelisch M, Andressen C, Addicks K, Hescheler J. Regulation of the L-type Ca2+ channel during cardiomyogenesis: Switch from NO to adenylyl cyclase-mediated inhibition. FASEB J 1999;13:313-324.Google Scholar
  78. 78.
    Paolocci N, Ekelund UEG, Isoda T, Ozaki M, Vandegaer K, Georgakopoulos D, Harrison R, Kass DA, Hare JM. cGMP-independent inotropic effect of nitric oxide and peroxynitirite donors: Potential role for S-nitrosylation. Am J Physiol 2000;279:H1982-H1988.Google Scholar
  79. 79.
    Balligand J-L, Kelly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci USA 1993;90:347-351.Google Scholar
  80. 80.
    Keaney JF Jr, Hare JM, Kelly RA, Loscalzo J, Smith TW, Colucci WS. Inhibition of nitric oxide synthase potentiates the positive inotropic response to ?-adrenergic stimulation in normal dogs. Am J Physiol 1996;271:H2646- H2652.Google Scholar
  81. 81.
    Kanai AJ, Mesaros S, Finkel MS, Oddis CV, Birder LA, Malinski T. ?-Adrenergic regulation of constitutive nitric oxide synthase in cardiac myocytes. Am J Physiol 1997;273:C1371-C1377.Google Scholar
  82. 82.
    Gauthier C, Leblais V, Kobzik L, Trochu J, Khandoudi N, Bril A, Balligand J-L, Le Marec H. The negative inotropic effect of ?3-adrenoreceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J Clin Invest 1998;102:1377-1384.Google Scholar
  83. 83.
    Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H. Functional ?3-adrenoceptor in the human heart. J Clin Invest 1998;98:556-562.Google Scholar
  84. 84.
    Gauthier C, Leblais V, Kobzik L, Trochu J-N, Khandoudi N, Bril A, Balligand J-L, LeMarec. H. The negative inotropic effect of ?3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J Clin Invest 1998;102:1377-1384.Google Scholar
  85. 85.
    Gauthier C, Tavernier G, Trochu J, Leblais V, Laurent K, Langin D, Escande D, Le Marec H. Interspecies differences in the cardiac negative inotropic effects of ?3-adrenoreceptor agonists. J Pharmacol Exp Ther 1999;290:687-693.Google Scholar
  86. 86.
    Moniotte S, Kobzik L, Feron O, Trochu JN, Gauthier C, Balligand JL. Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation 2001;103:1649-1655.Google Scholar
  87. 87.
    Shen Y-T, Cervoni P, Claus T, Vatner SF. Differences in ?3-adrenergic receptor cardiovascular regulation in conscious primates, rats and dogs. J Pharmacol Exp Ther 1996;278:1435-1443.Google Scholar
  88. 88.
    Varghese P, Harrison RW, Lofthouse RA, Georgakopoulos D, Berkowitz DE, Hare JM. Beta(3)-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility. J Clin Invest 2000;106:697-703.Google Scholar
  89. 89.
    Hare JM, Loh E, Creager MA, Colucci WS. Nitric oxide inhibits the contractile response to ?-adrenergic stimulation in humans with left ventricular dysfunction. Circulation 1995;92:2198-2203.Google Scholar
  90. 90.
    Wittstein IS, Kass DA, Maughan WL, Pak PH, Fetics B, Hare JM. Cardiac nitric oxide production due to angiotensin converting-enzyme inhibition decreases ?-adrenergic myocardial contractility in patients with dilated cardiomyopathy. J Am Coll Cardiol 2001;38:429- 435.Google Scholar
  91. 91.
    Prabhu SD, Azimi A, Frosto T. Nitric oxide effects on myocardial function and force-interval relations: Regulation of twitch duration. JMol Cell Cardiol 1999;31:2077-2085.Google Scholar
  92. 92.
    Prabhu SD, Freeman GL. Effect of tachycardia heart failure on the restitution of left ventricular function in closedchest dogs. Circulation 1995;91:176-185.Google Scholar
  93. 93.
    Kaye DM, Wiviott SD, Balligand J-L, Simmons WW, Smith TW, Kelly RA. Frequency-dependent activation of a constitutive nitric oxide synthase and regulation of contractile function in adult rat ventricular myocytes. Circ Res 1996;78:217-224.Google Scholar
  94. 94.
    Finkel MS, Oddis CV, Mayer OH, Hattler BG, Simmons RL. Nitric oxide synthase inhibitor alters papillary muscle force-frequency relationship. J Pharmacol Exp Ther 1995;272:945-952.Google Scholar
  95. 95.
    Harrison RW, Skaf MW, Berkowitz DE, Shoukas AA, Hare JM. Cardiac nitric oxide synthase 1 preserves the forcefrequency response in mice. Circulation 2001;104:II-436 (Abstract).Google Scholar
  96. 96.
    Ishihara H, Yokota M, Sobue T, Saito H. Relation between ventriculoarterial coupling and myocardial energetics in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994;23:406-416.Google Scholar
  97. 97.
    Ekelund UEG, Harrison RW, Shokek O, Thakkar RN, Tunin RS, Senzaki H, Kass DA, Marbán E, Hare JM. Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure. Circ Res 1999;85:437- 445.Google Scholar
  98. 98.
    Wolff MR, Buck SH, Stoker SW, Greaser ML, Mentzer RM. Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: Role of altered beta-adrenergically mediated protein phosphorylation. J Clin Invest 1996;98:167-176.Google Scholar
  99. 99.
    Wolff MR, De Tombe PP, Harasawa Y, Burkhoff D, Bier S, Hunter WC, Gerstenblith G, Kass DA. Alterations in left ventricular mechanics, energetics, and contractile reserve in experimental heart failure. Circ Res 1992;70:516-529.Google Scholar
  100. 100.
    Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 1999;85:357-363.Google Scholar
  101. 101.
    Saugstad OD. Role of xanthine oxidase and its inhibitor in hypoxia: Reoxygenation injury. Pediatrics 1996;98:103-107.Google Scholar
  102. 102.
    de Jong JW. Xanthine oxidoreductase activity in perfused hearts of various species, including humans. Circ Res 1990;67:770-773.Google Scholar
  103. 103.
    Cappola TP, Kass DA, Nelson GS, Berger RD, Rosas GO, Kobeissi ZA, Marban E, Hare JM. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation 2001;104:2407-2411.Google Scholar
  104. 104.
    Xu KY, Zweier JL, Becker LC. Functional coupling between glycolysis and sarcoplasmic reticulum Ca2+ transport. Circ Res 1995;77:88-97.Google Scholar
  105. 105.
    Xu L, Mann GE, Meissner G. Regulation of cardiac Ca2+ release channel (ryanodine receptor) by Ca2+, H+, Mg2+, and adenine nucleotides under normal and simulated ischemic conditions. Circ Res 1996;79:1100-1109.Google Scholar
  106. 106.
    Clementi E, Brown GC, Foxwell N, Moncada S. On the mechanism by which vascular endothelial cells regulate their oxygen consumption. Proc Natl Acad Sci USA 1999;96:1559-1562.Google Scholar
  107. 107.
    Eu JP, Sun J, Xu L, Stamler JS, Meissner G. The skeletal muscle calcium release channel: Coupled O2 sensor and NO signaling functions. Cell 2000;102:499-509.Google Scholar
  108. 108.
    Eu JP, Xu L, Stamler JS, Meissner G. Regulation of ryanodine receptors by reactive nitrogen species. Biochemical Pharmacology 1999;57:1079-1084.Google Scholar
  109. 109.
    Takasago T, Goto Y, Kawaguichi O, Hata K, Saeki A, Nishioka T, Suga H. Ryanodine wastes oxygen consumption for Ca2+ handling in the dog heart. J Clin Invest 1993;92:823-830.Google Scholar
  110. 110.
    Shinke T, Takaoka H, Takeuchi M, Hata K, Kawai H, Okubo H, Kijima Y, Murata T, Yokoyama M. Nitric oxide spares myocardial oxygen consumption through attenuation of contractile response to beta-adrenergic stimulation in patients with idiopathic dilated cardiomyopathy. Circulation 2000;101:1925-1930.Google Scholar
  111. 111.
    Balligand J-L, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 1993;91:2314-2319.Google Scholar
  112. 112.
    Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993;73:413-467.Google Scholar
  113. 113.
    Hare JM, Colucci WS. Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis 1995;38:155- 166.Google Scholar
  114. 114.
    Feron O, Smith TW, Michel T, Kelly RA.Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J Biol Chem 1997;272:17744-17748.Google Scholar
  115. 115.
    Schwencke C, Okumura S, Yamamoto M, Geng YJ, Ishikawa Y. Colocalization of beta-adrenergic receptors and caveolin within the plasma membrane. J Cell Biochem 1999;75:64-72.Google Scholar
  116. 116.
    Schwencke C, Yamamoto M, Okumura S, Toya Y, Kim SJ, Ishikawa Y. Compartmentation of cyclic adenosine 3',5'-monophosphate signaling in caveolae. Mol Endocrinol 1999;13:1061-1070.Google Scholar
  117. 117.
    Yamamoto M, Okumura S, Oka N, Schwencke C, Ishikawa Y. Downregulation of caveolin expression by cAMP signal. Life Sci 1999;64:1349-1357.Google Scholar
  118. 118.
    Brodde OE. Beta-adrenoceptors in cardiac disease. Pharmacol Ther 1993;60:405-430.Google Scholar
  119. 119.
    Cheng HJ, Zhang ZS, Onishi K, Ukai T, Sane DC, Cheng CP. Upregulation of functional beta(3)-adrenergic receptor in the failing canine myocardium. Circ Res 2001;89:599-606.Google Scholar
  120. 120.
    Hart CY, Hahn EL, Meyer DM, Burnett JC Jr, Redfield MM. Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs. Am J Physiol Heart Circ Physiol 2001;281:H146-H154.Google Scholar
  121. 121.
    Senzaki H, Smith CJ, Juang GJ, Isoda T, Mayer SP, Ohler A, Paolocci N, Tomaselli GF, Hare JM, Kass DA. Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. FASEB J 2001;15:1718-1726.Google Scholar
  122. 122.
    Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, Huang F, Xia H, Peters MF, Froehner SC, Bredt DS. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and ?1-syntrophin mediated by PDZ domains. Cell 1996;84:757-767.Google Scholar
  123. 123.
    Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH. Dexras 1: A G protein specifically coupled to neuronal nitric oxide synthase via CAPON. Neuron 2000;28:183-193.Google Scholar
  124. 124.
    Kanai AJ, Pearce LL, Clemens PR, Birder LA, VanBibber MM, Choi SY, de Groat WC, Peterson J. Identification of a neuronal nitric oxide synthase in isolated cardiac mitochondria using electrochemical detection. Proc Natl Acad Sci USA 2001;98:14126-14131.Google Scholar
  125. 125.
    Calderone A, Thaik CM, Takahashi N, Chang DLF, Colucci WS. Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest 1998;101:812-818.Google Scholar
  126. 126.
    Yang XP, Liu YH, Shesely EG, Bulagannawar M, Liu F, Carretero OA. Endothelial nitric oxide gene knockout mice: Cardiac phenotypes and the effect of angiotensin-converting enzyme inhibitor on myocardial ischemia/reperfusion injury. Hypertension 1999;34:24- 30.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Hunter C. Champion
    • 1
  • Michel W. Skaf
    • 1
  • Joshua M. Hare
    • 1
  1. 1.Division of Cardiology, Department of MedicineJohns Hopkins HospitalBaltimoreUSA

Personalised recommendations