Nitric oxide signaling: Systems integration of oxygen balance in defense of cell integrity

Current Opinion in Hematology

Volumn 11, Issue 1, 2004, Pages 7-14

  Gong, Li ^a   Pitari, Giovanni M ^a   Schulz, Stephanie ^a   Waldman, Scott A ^a,b  

^a THOMAS JEFFERSON UNIVERSITY   (United States)

^b THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Atherogenesis; Cell and tissue homeostasis; Cell energetics; Compartmentalization; Cyclic GMP; Endothelial dysfunction; Guanylyl cyclase; Nitric oxide; Nitric oxide synthases; Oxygen balance; S nitrosylation; Systems integration

Indexed keywords

ADENOSINE TRIPHOSPHATE; CYCLIC GMP; CYTOCHROME C OXIDASE; HEMOGLOBIN; NITRIC OXIDE; NITRIC OXIDE SYNTHASE;

CALCIUM CONDUCTANCE; CELL ENERGY; CELL FUNCTION; CELL METABOLISM; CELL RESPIRATION; COMPLEX FORMATION; DOWN REGULATION; ENERGY CONSUMPTION; ENERGY RESOURCE; ENERGY YIELD; HYPOXIC CELL; MUSCLE CONTRACTILITY; NITROSYLATION; NONHUMAN; OXIDATION; OXYGEN CONSUMPTION; OXYGEN SATURATION; OXYGEN SUPPLY; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN PROCESSING; REDUCTION; REVIEW; SIGNAL TRANSDUCTION; TISSUE OXYGENATION; VASCULAR SMOOTH MUSCLE;

ANIMALS; CARDIOVASCULAR PHYSIOLOGY; CARDIOVASCULAR SYSTEM; CELL HYPOXIA; CYCLIC GMP; GUANYLATE CYCLASE; HUMANS; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; OXIDATIVE PHOSPHORYLATION; OXYGEN CONSUMPTION; RECEPTORS, CYTOPLASMIC AND NUCLEAR; SIGNAL TRANSDUCTION;

EID: 0346880067     PISSN: 10656251     EISSN: None     Source Type: Journal    
DOI: 10.1097/00062752-200401000-00003     Document Type: Review

References (86)

1. Ignarro LJ: Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J Physiol Pharmacol 2002, 53:503-514. Recent review, with historical perspective, of NO signaling in the cardiovascular system authored by one of the 1998 Nobel Laureates in Physiology or Medicine.
2. Stamler JS, Lamas S, Fang FC: Nitrosylation, the prototypic redox-based signaling mechanism. Cell 2001, 106:675-683.
3. Friebe A, Koesling D: Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 2003, 93:96-105. Recent comprehensive review of mechanisms underlying NO regulation of guanylyl cyclases.
4. Lucas KA, Pitari GM, Kazerounian S, et al.: Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 2000, 52:375-414.
5. Martin E, Sharina I, Kots A, Murad F: A constitutively activated mutant of human soluble guanylyl cyclase (sGC): implication for the mechanism of sGC activation. Proc Natl Acad Sci U S A 2003, 100:9208-9213. First description of the role of the heme prosthetic group as a constitutive inhibitor of NO-sensitive guanylyl cyclase.
6. Wielinga PR, van der Heijden I, Reid G, et al.: Characterization of the MRP4-and MRP5-mediated transport of cyclic nucleotides from intact cells. J Biol Chem 2003, 278:17664-17671. Demonstrates the minimum contribution of regulated efflux to stead-state intracellular cGMP concentrations.
7. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA: Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003, 93:280-291. Recent review of the role of phosphodiesterases in regulating vascular smooth muscle contractility.
8. Rybalkin SD, Rybalkina IG, Shimizu-Albergine M, et al.: PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO J 2003, 22:469-478.
9. Mullershausen F, Friebe A, Feil R, et al.: Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling. J Cell Biol 2003, 160:719-727. This and the prior citation describe a novel mechanism regulating PDE5, in which cGMP mediates a reinforcing feedback mechanism that serves as a "gain control" that shapes subsequent cGMP responses to NO in the context of the amplitude and duration of prior responses.
10. Schlossmann J, Feil R, Hofmann F: Signaling through NO and cGMP-dependent protein kinases. Ann Med 2003, 35:21-27. A recent review of the role of cGMP-dependent protein kinase in regulating vascular smooth muscle contractility.
11. Tiyyagura S, Kazerounian S, Schulz S, et al.: Integration of cyclic GMP and calcium signaling. Vitam Horm 2003, (In press) A recent review highlighting the regulation of opposing physiological mechanisms by cGMP and calcium, reflected in the reciprocal regulation of their intracellular concentrations.
12. Schmachtenberg O, Diaz J, Bacigalupo J: NO activates the olfactory cyclic nucleotide-gated conductance independent from cGMP in isolated rat olfactory receptor neurons. Brain Res 2003, 980:146-150.
13. Aizawa T, Wei H, Miano JM, et al.: Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. Circ Res 2003, 93:406-413. The first demonstration of a role for PDE3 as a downstream effector of NO-dependent increases in cGMP, increasing intracellular concentrations of cAMP, inhibiting gene expression characteristic of inflammation in smooth muscle cells, a fundamental process underlying atherogenesis.
14. Kojda G, Kottenberg K, Nix P, et al.: Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes. Circ Res 1996, 78:91-101.
15. Gustafsson AB, Brunton LL: Attenuation of cAMP accumulation in adult rat cardiac fibroblasts by IL-1beta and NO: role of cGMP-stimulated PDE2. Am J Physiol Cell Physiol 2002, 283:C463-C471. The first suggestion that inflammation in the myocardium induces negative inotropy associated with heart failure by NO-dependent increases in cGMP activating PDE2, resulting in a reduction in cardiomyocyte cAMP.
16. Moncada S, Erusalimsky JD: Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat Rev Mol Cell Biol 2002, 3:214-220. Outstanding summary of the role of NO in regulating oxygen consumption by the mitochondrial respiratory chain and the divergent mechanisms mediating mitochondria-associated apoptosis.
17. Giulivi C: Characterization and function of mitochondrial nitric-oxide synthase. Free Radic Biol Med 2003, 34:397-408. This is a comprehensive review of mitochondrial NOS, its functional characteristics and regulation, and its role in transmitting the oxygen gradient from perivascular cells to those distal to vessels by inhibition of cytochrome oxidase.
18. Nedospasov A, Rafikov R, Beda N, Nudler E: An autocatalytic mechanism of protein nitrosylation. Proc Natl Acad Sci U S A 2000, 97:13543-13548.
19. Broillet MC: A single intracellular cysteine residue is responsible for the activation of the olfactory cyclic nucleotide-gated channel by NO. J Biol Chem 2000, 275:15135-15141.
20. Williams JG, Pappu K, Campbell SL: Structural and biochemical studies of p21Ras S-nitrosylation and nitric oxide-mediated guanine nucleotide exchange. Proc Natl Acad Sci U S A 2003, 100:6376-6381. An example of posttranslational modification by targeted S-nitrosylation regulating signaling. Indeed, S-nitrosylation interferes with interactions that stabilize the GDP-bound conformation of Ras, producing guanine nucleotide exchange.
21. Sun J, Xin C, Eu JP, et al.: Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO. Proc Natl Acad Sci USA 2001, 98:11158-11162. Demonstrates the precision of posttranslational modification mediated by NO and S-nitrosylation modulated by oxygen-dependent allostery. The ryanodine receptor has >50 cysteines available for modification. However, oxygen maintains only a subset available in the appropriate redox state for modification, while one, Cys3635 in the calmodulin-binding domain, is modified by S-nitrosylation, reflecting the structural specificity of the modification.
22. Gow AJ, Chen Q, Hess DT, et al.: Basal and stimulated protein S-nitrosylation in multiple cell types and tissues. J Biol Chem 2002, 277:9637-9640. Describes the coupling of S-nitrosylation to the activity of each isoform of NOS in multiple cell types and tissues including endothelial, smooth muscle, neuronal cells, macrophages, as well as human lung.
23. Matsumoto A, Comatas KE, Liu L, Stamler JS: Screening for nitric oxide-dependent protein-protein interactions. Science 2003, 301:657-661. First demonstration that S-nitrosylation of proteins by NO can lead to a broad-based mechanism for regulating interactions between proteins. Identifies multiple NO-dependent protein-protein interactions employing a modified yeast two-hybrid system and mammalian cells.
24. Alderton WK, Cooper CE, Knowles RG: Nitric oxide synthases: structure, function and inhibition. Biochem J 2001, 357:593-615.
25. Kone BC, Kuncewicz T, Zhang W, Yu ZY: Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide. Am J Physiol Renal Physiol 2003, 285:F178-F190. Outstanding review of the spatial and temporal precision and specificity of signal initiation, amplification, and propagation by NO, orchestrated by dynamic assembly of supramolecular complexes coupling NO production to upstream and downstream components in specific subcellular compartments.
26. Shaul PW: Regulation of endothelial nitric oxide synthase: location, location, location. Annu Rev Physiol 2002, 64:749-774. Detailed review of eNOS structure and function, with emphasis on the regulation of signaling in macromolecuiar complexes organized within caveolae.
27. Tomita S, Nicoll RA, Bredt DS: PDZ protein interactions regulating glutamate receptor function and plasticity. J Cell Biol 2001, 153:F19-F24.
28. Bustamante J, Bersier G, Badin RA, et al.: Sequential NO production by mitochondria and endoplasmic reticulum during induced apoptosis. Nitric Oxide 2002, 6:333-341.
29. Lacza Z, Puskar M, Figueroa JP, et al.: Mitochondrial nitric oxide synthase is constitutively active and is functionally upregulated in hypoxia. Free Radic Biol Med 2001, 31:1609-1615.
30. Carreras MC, Peralta JG, Converse DP, et al.: Modulation of liver mitochondrial NOS is implicated in thyroid-dependent regulation of O(2) uptake. Am J Physiol Heart Circ Physiol 2001, 281:H2282-H2288.
31. Goligorsky MS, Li H, Brodsky S, Chen J: Relationships between caveolae and eNOS: everything in proximity and the proximity of everything. Am J Physiol Renal Physiol 2002, 283:F1-10. Comprehensive review of the subcellular localization of eNOS in caveolae and the associated dynamic regulation of signaling imposed by proximity to coregulators and effectors.
32. Burette A, Zabel U, Weinberg RJ, et al.: Synaptic localization of nitric oxide synthase and soluble guanylyl cyclase in the hippocampus. J Neurosci 2002, 22:8961-8970.
33. Bon CL, Garthwaite J: On the role of nitric oxide in hippocampal long-term potentiation. J Neurosci 2003, 23:1941-1948.
34. Chien WL, Liang KC, Teng CM, et al.: Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole. Mol Pharmacol 2003, 63:1322-1328.
35. Jaffrey SR, Benfenati F, Snowman AM, et al.: Neuronal nitric-oxide synthase localization mediated by a ternary complex with synapsin and CAPON. Proc Natl Acad Sci U S A 2002, 99:3199-3204. These three papers describe the role, anatomical localization, and regulation of NOS and NO-sensitive guanylyl cyclase at synapses in the central nervous system that mediate long-term potentiation, the basis of learning and memory. Importantly, whereas NOS is localized to postsynaptic membranes in dynamic macromolecuiar assemblies containing N-methyl-D-aspartate receptors and coregulators, such as CAPON, guanylyl cyclase is localized to the presynaptic membrane, mediating retrograde signaling to influence afferent neurons.
36. Drab M, Verkade P, Elger M, et al.: Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 2001, 293:2449-2452.
37. Razani B, Engelman JA, Wang XB, et al.: Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem 2001, 276:33121-38138.
38. Takahashi S, Mendelsohn ME: Calmodulin-dependent and -independent activation of endothelial nitric-oxide synthase by heat shock protein 90. J Biol Chem 2003, 278:9339-9344. Interaction of eNOS with Hsp90 is induced by a variety of stimuli, including receptor agonists and shear stress. Interaction results in the allosteric activation of eNOS, in part, by enhancing interaction with calmodulin.
39. Feron O, Saldana F, Michel JB, Michel T: The endothelial nitric-oxide synthase-caveolin regulatory cycle. J Biol Chem 1998, 273:3125-3128.
40. Fontana J, Fulton D, Chen Y, et al.: Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release. Circ Res 2002, 90:866-873. Activation of eNOS by Hsp90 is mediated by the dynamic formation of macromolecular signaling complexes. Indeed, the N-terminal of Hsp90 serves as a scaffold that approximates eNOS and AKT, resulting in phosphorylation of the former by the latter and activation of NO production, possibly by increasing calmodulin binding.
41. Zabel U, Kleinschnitz C, Oh P, et al.: Calcium-dependent membrane association sensitizes soluble guanylyl cyclase to nitric oxide. Nat Cell Biol 2002, 4:307-311. First description of a novel mechanism regulating NO-dependent guanylyl cyclase signaling in which calcium translocates NO-sensitive guanylyl cyclase from the cytoplasmic compartment to caveolae. Presumably, colocalization of guanylyl cyclase in caveolae with eNOS confers an additional level of control over the spatial and temporal regulation of cGMP production by NO.
42. Zimmermann K, Opitz N, Dedio J, et al.: NOSTRIN: a protein modulating nitric oxide release and subcellular distribution of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 2002, 99:17167-17172.
43. Dedio J, Konig P, Wohlfart P, et al.: NOSIP, a novel modulator of endothelial nitric oxide synthase activity. FASEB J 2001, 15:79-89.
44. Barouch LA, Harrison RW, Skaf MW, et al.: Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 2002, 416:337-339. The first demonstration of select regulation of NOS isoforms expressed in different subcellular compartments mediating opposing physiological responses in a single cell.
45. Griffiths C, Yamini B, Hall C, Garthwaite J: Nitric oxide inactivation in brain by a novel O2-dependent mechanism resulting in the formation of nitrate ions. Biochem J 2002, 362:459-464. Demonstration of the existence of a protein-based clearance mechanism for consuming NO that maintains steady-state concentrations of that signaling molecule in cells and determines its short biological half-life.
46. McMahon TJ, Moon RE, Luschinger BP, et al.: Nitric oxide in the human respiratory cycle. Nat Med 2002, 8:711-717. Innovative demonstration of the role of NO in regulating the respiratory cycle in humans through a redox-based mechanism modulated by oxygen-dependent allostery involving nitrosylation of the transition metal center and cysteine free thiols of hemoglobin to acquire and deliver oxygen.
47. Pawloski JR, Hess DT, Stamler JS: Export by red blood cells of nitric oxide bioactivity. Nature 2001, 409:622-626.
48. Hobbs AJ, Gladwin MT, Patel RP, et al.: Haemoglobin: NO transporter, NO Inactivator or NOne of the above? Trends Pharmacol Sci 2002, 23:406-411.
49. Crawford JH, White CR, Patel RP: Vasoactivity of S-nitrosohemoglobin: role of oxygen, heme, and NO oxidation states. Blood 2003, 101:4408-4415.
50. Gladwin MT, Lancaster JR Jr, Freeman BA, Schechter AN: Nitric oxide's reactions with hemoglobin: a view through the SNO-storm. Nat Med 2003, 9:496-500.
51. Joshi MS, Ferguson TB Jr, Han TH, et al.: Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions. Proc Natl Acad Sci U S A 2002, 99:10341-10346.
52. Rassaf T, Bryan NS, Maloney RE, et al.: NO adducts in mammalian red blood cells: too much or too little? Nat Med 2003, 9:481-482.
53. Dzeja PP, Terzic A: Phosphotransfer networks and cellular energetics. J Exp Biol 2003, 206:2039-2047. Outstanding synthesis of the regulation and function of energetic signaling by high energy phosphoryl "wires," and their coupling to metabolic and cell signaling mechanisms.
54. Lee JM, Grabb MC, Zipfel GJ, Choi DW: Brain tissue responses to ischemia. J Clin Invest 2000, 106:723-731.
55. Bellamy TC, Griffiths C, Garthwaite J: Differential sensitivity of guanylyl cyclase and mitochondrial respiration to nitric oxide measured using clamped concentrations. J Biol Chem 2002, 277:31801-31807. These observations suggest that NO signaling in cells is selectively targeted to cGMP responses, rather than inhibition of cytochrome oxidase, reflecting the differential sensitivity of guanylyl cyclase, which is nearly two orders of magnitude more sensitive to NO compared to cytochrome oxidase under normoxic conditions, and the maximum concentrations of NO achieved in cells, which is well below the binding constant for cytochrome oxidase under normoxic conditions. Indeed, these data argue for a specific role for mitochondrial NOS in regulating cytochrome oxidase, ATP generation, and oxygen consumption.
56. Zweier JL, Wang P, Kuppusamy P: Direct measurement of nitric oxide generation in the ischemic heart using electron paramagnetic resonance spectroscopy. J Biol Chem 1995, 270:304-307.
57. Depre C, Gaussin V, Ponchaut S, et al.: Inhibition of myocardial glucose uptake by cGMP. Am J Physiol 1998, 274:H1443-H1449.
58. Tada H, Thompson CI, Recchia FA, et al.: Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart. Circ Res 2000, 86:270-274.
59. Recchia FA, McConnell PI, Loke KE, et al.: Nitric oxide controls cardiac substrate utilization in the conscious dog. Cardiovasc Res 1999, 44:325-332.
60. Bernstein RD, Ochoa FY, Xu X, et al.: Function and production of nitric oxide in the coronary circulation of the conscious dog during exercise. Circ Res 1996, 79:840-848.
61. Shen W, Tian R, Saupe KW, et al.: Endogenous nitric oxide enhances coupling between O2 consumption and ATP synthesis in guinea pig hearts. Am J Physiol Heart Circ Physiol 2001, 281:H838-H846.
62. Almeida A, Almeida J, Bolanos JP, Moncada S: Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Natl Acad Sci U S A 2001, 98:15294-15299.
63. Nisoli E, Clementi E, Paolucci C, et al.: Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 2003, 299:896-899. Provides the first evidence that NO stimulates mitochondrial biogenesis in a number of cell lines through a cGMP-dependent signaling pathway that activates PGC1α, a master regulator of mitochondrial content. These observations suggest the possibilities of a role for NO in modulating mitochondrial content in response to physiological stimuli.
64. Sandau KB, Fandrey J, Brune B: Accumulation of HIF-1alpha under the influence of nitric oxide. Blood 2001, 97:1009-1015.
65. Teodoro RO, O'Farrell PH: Nitric oxide-induced suspended animation promotes survival during hypoxia. EMBO J 2003, 22:580-587. Novel observation in fly larvae demonstrating that severe hypoxic stress results in complete, but reversible, cessation of energy-consuming activities, a type of "suspended animation," mediated by NO through a cGMP-independent signaling mechanism.
66. Hamad AM, Clayton A, Islam B, Knox AJ: Guanylyl cyclases, nitric oxide, natriuretic peptides, and airway smooth muscle function. Am J Physiol Lung Cell Mol Physiol 2003, 285:L973-L983. Recent comprehensive review of the role of cGMP in regulating airway smooth muscle contractility.
67. Pulido EJ, Shames BD, Selzman CH, et al.: Inhibition of PARS attenuates endotoxin-induced dysfunction of pulmonary vasorelaxation. Am J Physiol 1999, 277:L769-L776.
68. Guth BD, Schulz R, Heusch G: Time course and mechanisms of contractile dysfunction during acute myocardial ischemia. Circulation 1993, 87:IV35-IV42.
69. Schleiffer R, Raul F: Prophylactic administration of L-arginine improves the intestinal barrier function after mesenteric ischaemia. Gut 1996, 39:194-198.
70. Rivera-Chavez FA, Toledo-Pereyra LH, Dean RE, et al.: Exogenous and endogenous nitric oxide but not iNOS inhibition improves function and survival of ischemically injured livers. J Invest Surg 2001, 14:267-273.
71. Verma S, Anderson TJ: Fundamentals of endothelial function for the clinical cardiologist. Circulation 2002, 105:546-549. A review outlining the role of endothelial dysfunction and abnormalities in NO signaling in atherogenesis and ischemic cardiovascular disease.
72. Cooke JP: Flow, NO, and atherogenesis. Proc Natl Acad Sci U S A 2003, 100:768-770. An outstanding brief summary of the genesis of endothelial dysfunction, including the role of abnormal shear stress in promoting dysfunction, the loss of NO bioactivity associated with abnormal endothelial function, and the contribution of abnormal NO signaling to progression to atherogenesis and ischemic cardiovascular disease.
73. Schachinger V, Britten MB, Zeiher AM: Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000, 101:1899-1906.
74. Ross R: Atherosclerosis-an inflammatory disease. N Engl J Med 1999, 340:115-126.
75. Blair A, Shaul PW, Yuhanna IS, et al.: Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J Biol Chem 1999, 274:32512-32519.
76. de Nigris F, Lerman LO, Ignarro SW, et al.: Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress. Proc Natl Acad Sci USA 2003, 100:1420-1425. Demonstration that arginine supplementation blocks the expression of genes associated with dysfunction in endothelial cells in vitro and in mouse models of atherogenesis in vivo. These studies provide a rationale for the continued focus on NO signaling, and arginine supplementation specifically, in approaches to treating patients with atherogenesis and ischemic cardiovascular diseases.
77. Napoli C, Ignarro LJ: Nitric oxide and atherosclerosis. Nitric Oxide 2001, 5:88-97.
78. Maxwell AJ, Ho HV, Le CQ, et al.: L-arginine enhances aerobic exercise capacity in association with augmented nitric oxide production. J Appl Physiol 2001, 90:933-938.
79. Bode-Boger SM, Boger RH, Kienke S, et al.: Chronic dietary supplementation with L-arginine inhibits platelet aggregation and thromboxane A2 synthesis in hypercholesterolaemic rabbits in vivo. Cardiovasc Res 1998, 37:756-764.
80. Maxwell AJ, Zapien MP, Pearce GL, et al.: Randomized trial of a medical food for the dietary management of chronic, stable angina. J Am Coll Cardiol 2002, 39:37-45.
81. Lerman A, Burnett JC Jr, Higano ST, et al.: Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998, 97:2123-2128.
82. Fujita H, Yamabe H, Yokoyama M: Effect of L-arginine administration on myocardial thallium-201 perfusion during exercise in patients with angina pectoris and normal coronary angiograms. J Nucl Cardiol 2000, 7:97-102.
83. Tousoulis D, Davies GJ, Tentolouris C, et al.: Effects of changing the availability of the substrate for nitric oxide synthase by L-arginine administration on coronary vasomotor tone in angina patients with angiographically narrowed and in patients with normal coronary arteries. Am J Cardiol 1998, 82:1110-1113, A1116.
84. Blum A, Hathaway L, Mincemoyer R, et al.: Oral L-arginine in patients with coronary artery disease on medical management. Circulation 2000, 101:2160-2164.
85. Dzau VJ, Bernstein K, Celermajer D, et al.: Pathophysiologic and therapeutic importance of tissue ACE: a consensus report. Cardiovasc Drugs Ther 2002, 16:149-160.
86. Takemoto M, Liao JK: Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001, 21:1712-1719.