The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function

Vascular Medicine

Volumn 7, Issue 3, 2002, Pages 213-225

  Maas, Renke ^a   Schwedhelm, Edzard ^a   Albsmeier, Jennifer ^a   Böger, Rainer H ^a  

^a UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

Author keywords

Asymmetrical dimethylarginine; Endothelial dysfunction; Endothelin; Erectile dysfunction; Nitric oxide; Nitric oxide synthase; Oxidative stress; Prostaglandin

Indexed keywords

ANGIOTENSIN; ARGININE; BMS 1938; ENDOTHELIN; ENDOTHELIN A RECEPTOR ANTAGONIST; ENDOTHELIUM DERIVED HYPERPOLARIZING FACTOR; ICOSANOID; KININ; N(G),N(G) DIMETHYLARGININE; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; NITRIC OXIDE SYNTHASE INHIBITOR; PROSTAGLANDIN; UNCLASSIFIED DRUG;

ATHEROSCLEROSIS; BLOOD LEVEL; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CLINICAL TRIAL; DIABETES MELLITUS; DISEASE ASSOCIATION; DOSE RESPONSE; ENDOTHELIUM LESION; ENZYME INHIBITION; ENZYME REGULATION; ERECTILE DYSFUNCTION; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; INCIDENCE; KIDNEY FAILURE; MEDIATOR; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PATHOPHYSIOLOGY; PENIS ERECTION; PRIORITY JOURNAL; REVIEW; SENESCENCE; SMOKING; SMOOTH MUSCLE CONTRACTION; SMOOTH MUSCLE RELAXATION; VASCULAR ENDOTHELIUM; VASODILATATION;

ENDOTHELIUM, VASCULAR; EVIDENCE-BASED MEDICINE; GREAT BRITAIN; HUMANS; IMPOTENCE; INCIDENCE; MALE; MUSCLE RELAXATION; MUSCLE, SMOOTH, VASCULAR; NITRIC OXIDE; UNITED STATES;

EID: 0036961308     PISSN: 1358863X     EISSN: None     Source Type: Journal    
DOI: 10.1191/1358863x02vm429ra     Document Type: Review

References (230)

1. NIH consensus development panel on impotence. NIH consensus conference: Impotence. JAMA 1993; 270: 83-90.
2. Green JS, Holden ST, Ingram P, Bose P, St. George DP, Browsher WG. An investigation of erectile dysfunction in Gwent, Wales. BJU Int 2001; 88: 551-53.
3. Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999; 84: 50-56.
4. Moreira ED Jr, Abdo CH, Torres EB, Lobo CF, Fittipaldi JA. Prevalence and correlates of erectile dysfunction: Results of the Brazilian study of sexual behavior. Urology 2001; 58: 583-88.
5. Rosas SE, Joffe M, Franklin E et al. Prevalence and determinants of erectile dysfunction in hemodialysis patients. Kidney Int 2001; 59: 2259-66.
6. Parazzini F, Menchini Fabris F et al. Frequency and determinants of erectile dysfunction in Italy. Eur Urol 2000; 37: 43-49.
7. Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: 1802-13.
8. Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: Longitudinal results from the Massachussetts male aging study. J Urol 2000; 163: 460-63.
9. Sullivan ME, Thompson CS, Dashwood MR et al. Nitric oxide and penile erection: Is erectile dysfunction another manifestation of vascular disease? Cardiovasc Res 1999; 43: 658-65.
10. Sullivan ME, Koeghane SR, Miller MA. Vascular risk factors and erectile dysfunction. BJU Int 2001; 87: 838-45.
11. Brock GB, Lue TF. Drug-induced male sexual dysfunction. An update. Drug Saf 1993; 8: 414-26.
12. Jensen J, Lendorf A, Stimpel H, Frost J, Ibsen H, Rosenkilde P. The prevalence and etiology of impotence in 101 male hypertensive outpatients. Am J Hypertens 1999; 12: 271-75.
13. Fedele D, Coscelli C, Cucinotta D et al. Incidence of erectile dysfunction in Italian men with diabetes. J Urol 2001; 166: 1368-71.
14. Siu SC, Lo SK, Wong KW, Ip KM, Wong YS. Prevalence of and risk factors for erectile dysfunction in Hong Kong diabetic patients. Diabet Med 2001; 18: 732-38.
15. Martin-Morales A, Sanchez-Cruz JJ, Saenz De Tejada I, Rodriguez-Vela L, Jimenez-Cruz JF, Burgos-Rodriguez R. Prevalence and independent risk factors for erectile dysfunction in Spain: Results of the Epidemiologia de la Disfunction Erectil Masculina study. J Urol 2001; 166: 569-74.
16. McCulloch DK, Campbell IW, Wu FC, Prescott RJ, Clarke BF. The prevalence of diabetic impotence. Diabetologia 1980; 18: 279-83.
17. Wei M, Macera CA, Davis DR, Hornung CA, Nankin HR, Blair SN. Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. Am J Epidemiol 1994; 140: 930-37.
18. Virag R, Bouilly P, Frydman D. Is impotence an arterial disorder? A study of arterial risk factors in 440 impotent men. Lancet 1985; i: 181-84.
19. Palmer BF. Sexual dysfunction in uraemia. J Am Soc Nephrol 1999; 10: 1381-88.
20. Procci WR, Goldstein DA, Adelstein J, Massry SG. Sexual dysfunction in the male patient with uraemia: A reappraisal. Kidney Int 1981; 19: 317-23.
21. Türk S, Karalezli G, Tonbul HZ et al. Erectile dysfunction and the effects of sildenafil treatment in patients on haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2001; 16: 1818-22.
22. Kuvin JT, Patel AR, Sliney KA et al. Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol 2001; 38: 1843-49.
23. Hashimoto M, Kozaki K, Eto M et al. Association of coronary risk factors and endothelium-dependent flow-mediated dilatation of the brachial artery. Hypertens Res 2000; 23: 233-38.
24. Egashira K, Inou T, Hirooka Y et al. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993; 91: 29-37.
25. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993; 87: 1468-74.
26. Thorne S, Mullen MJ, Clarkson P, Donald AE, Deanfield JE. Early endothelial dysfunction in adults at risk from atherosclerosis: Different responses to L-arginine. J Am Coll Cardiol 1998; 32: 110-16.
27. Preik M, Kelm M, Rosen P, Tschöpe D, Strauer BE. Additive effect of coexistent type 2 diabetes and arterial hypertension on endothelial dysfunction in resistance arteries of human forearm vasculature. Angiology 2000; 51: 545-54.
28. Van Guldener C, Janssen MJ, Lambert J, Steyn M, Donker AJ, Stehouwer CD. Endothelium-dependent vasodilatation is impaired in peritoneal dialysis patients. Nephrol Dial Transplant 1998; 13: 1782-86.
29. Morris ST, McMurray JJ, Spiers A, Jardine AG. Impaired endothelial function in isolated human uremic resistance arteries. Kidney Int 2001; 60: 1077-82.
30. Kaufmann PA, Gnecchi-Ruscone T, Schäfers KP, Lüscher TF, Camici PG. Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolaemia. J Am Coll Cardiol 2000; 36: 103-109.
31. Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 1993; 92: 652-62.
32. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 1991; 338: 1546-50.
33. Celermajer DS, Adams MR, Clarkson P et al. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 1996; 334: 150-54.
34. Poredos lP, Orehek M, Tratnik E. Smoking is associated with dose-related increase of intima-media thickness and endothelial dysfunction. Angiology 1999; 50: 201-208.
35. Andrawis N, Jones DS, Abernethy DR. Aging is associated with endothelial dysfunction in human forearm vasculature. J Am Geriatr Soc 2000; 48: 193-98.
36. Egashira K, Inou T, Hirooka Y et al. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation 1993; 88: 77-81.
37. Böger RH, Bode-Böger SM, Thiele W, Junker W, Alexander K, Frölich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997; 95: 2068-74.
38. Böger RH, Bode-Böger SM, Szuba A et al. Asymmetric dimethylarginine (ADMA): A novel risk factor for endothelial dysfunction. Its role in hypercholesterolemia. Circulation 1998; 98: 1842-47.
39. Rubanyi GM. The role of the endothelium in cardiovascular homeostasis and disease. J Cardiovasc Pharmacol 1993; 22 (suppl): S1-S4.
40. De Meyer GR, Herman AG. Vascular endothelial dysfunction. Prog Cardiovasc Dis 1997; 39: 325-432.
41. Drexler H. Endothelial dysfunction: Clinical implications. Prog Cardiovasc Dis 1997; 39: 287-324.
42. Moncada S. Nitric oxide in the vasculature: Physiology and pathophysiology. Ann NY Acad Sci 1997; 881: 60-69.
43. Goligorsky MS, Noiri E, Tsukahara H, Budzikowski AS, Li H. A pivotal role of nitric oxide in endothelial cell dysfunction. Acta Physiol Scand 2000; 168: 33-40.
44. Burnett AL. Nitric oxide in the penis: Physiology and pathology. J Urol 1997; 157: 320-24.
45. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002-12.
46. Kelm M, Rath J. Endothelial dysfunction in human coronary circulation: Relevance of the L-arginine-NO pathway. Basic Res Cardiol 2001; 96: 107-27.
47. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 1992; 326: 90-94.
48. Kim N, Azadzoi KM, Goldstein I, Saenz De Tejada I. A nitric oxide-like factor mediates nonadrenergic-noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J Clin Invest 1991; 88: 112-18.
49. Minhas S, Cartledge J, Eardley I. The role of prostaglandins in penile erection. Prostaglandins Leukot Essent Fatty Acids 2000; 62: 137-46.
50. Porst H. The rationale for prostaglandin E1 in erectile failure: A survey of worldwide experience. J Urol 1996; 155: 802-815.
51. Saenz De Tejada I, Carson MP, De Las Morenas A, Goldstein I, Traish AM. Endothelin: Localization, synthesis, activity, and receptor types in human penile corpus cavernosum. Am J Physiol 1991; 261: H1078-85.
52. Becker AJ, Ückert S, Stief CG et al. Possible role of bradykinin and angiotensin II in the regulation of penile erection and detumenescence. Urology 2001; 57: 193-98.
53. Ayajiki K, Fujioka H, Okamura T. Mechanisms underlying endothelium-dependent, nitric oxide/prostacyclin-independent, acetylcholine-induced relaxation in canine corpus cavernosum. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 448-51.
54. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333: 664-66.
55. Palmer RM, Rees DD, Ashton DS, Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 1988; 153: 1251-56.
56. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of the endothelium derived-relaxing factor. Nature 1987; 327: 524-26.
57. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: A physiologic mediator of penile erection. Science 1992; 257: 401-403.
58. Gonzalez-Cadavid NF, Ignarro LJ, Rajfer J. Nitric oxide and the cyclic GMP system in the penis. Mol Urol 1999; 3: 51-59.
59. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1990; 170: 843-50.
60. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 1993; 75: 1273-86.
61. Burnett AL, Nelson RJ, Calvin DC et al. Nitric oxide-dependent penile erection in mice lacking neuronal nitric oxide synthase. Mol Med 1996; 2: 288-96.
62. Gonzalez-Cadavid NF, Burnett AL, Magee TR et al. Expression of penile neuronal nitric oxide synthase variants in the rat and mouse penile nerves. Biol Reprod 2000; 63: 704-14.
63. Burnett AL, Chang AG, Crone JK, Huang PL, Sezen SE. Noncholinergic penile erection in mice lacking the gene for endothelial nitric oxide synthase. J Androl 2002; 23: 92-97.
64. Escrig A, Marin R, Abreu P, Luiz Gonzalez-Mora J, Mas M. Changes in mating behavior, erectile function, and nitric oxide levels in penile corpora cavernosa in streptozotocin-diabetic rats. Biol Reprod 2002; 66: 185-89.
65. Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A 1977; 74: 3203-207.
66. Hedlund P, Aszodi A, Pfeifer A et al. Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc Natl Acad Sci U S A 2000; 97: 2349-54.
67. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338: 1397-404.
68. Padma-Nathan H, Hellstrom WJ, Kaiser FE et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997; 336: 1-7.
69. Surks HK, Mochizuki N, Kasai Y et al. Regulation of myosin phosphatase by a specific interaction with cGMP dependent protein kinase Iα. Science 1999; 286: 1583-87.
70. Rees RW, Ralph DJ, Royle M, Moncada S, Cellek S. Y-27632, an inhibitor of Rho-kinase, antagonizes noradrenergic contraction in the rabbit and human penile corpus cavernosum. Br J Pharmacol 2001; 133: 455-58.
71. Chitaley K, Wingard CJ, Webb RC et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med 2001; 7: 119-22.
72. Andersson KE, Wagner G. Physiology of penile erection. Physiol Rev 1995; 75: 191-236.
73. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: Structure, function and inhibition. Biochem J 2001; 357: 593-615.
74. Deves R, Boyd CA. Transporters for cationic amino acids in animal cells: Discovery, structure, and function. Physiol Rev 1998; 78: 487-545.
75. + carrier hCAT-2B. Nitric Oxide 1997; 1: 65-73.
76. Xiao S, Wagner L, Mahaney J, Baylis C. Uremic levels of urea inhibit L-arginine transport in cultured endothelial cells. Am J Physiol Renal Physiol 2001; 280: F989-95.
77. Cox JD, Kim NN, Traish AM, Christianson DW. Arginase-boronic acid complex highlights a physiological role in erectile function. Nat Struct Biol 1999; 6: 1043-47.
78. 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: 923-27.
79. Michel T, Feron O. Nitric oxide synthases: Which, where, how, and why? J Clin Invest 1997; 100: 2146-52.
80. Hedlund P, Ny L, Alm P, Andersson KE. Cholinergic nerves in human corpus cavernosum and spongiosum contain nitric oxide synthase and heme oxygenase. J Urol 2000; 164: 868-75.
81. Bloch W, Klotz T, Sedlaczek P, Zumbe J, Engelmann U, Addicks K. Evidence for the involvement of endothelial nitric oxide synthase from smooth muscle cells in the erectile function of the human corpus cavernosum. Urol Res 1998; 26: 129-35.
82. Dail WG, Barba V, Leyba L, Galindo R. Neural and endothelial nitric oxide synthase activity in rat penile erectile tissue. Cell Tissue Res 1995; 282: 109-16.
83. Förstermann U, Boissel JP, Kleinert H. Expressional control of the 'constitutive' isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J 1998; 12: 773-90.
84. Xiao Z, Zhang Z, Diamond SL. Shear stress induction of the endothelial nitric oxide synthase gene is calcium-dependent but not calcium-activated. J Cell Physiol 1997; 171: 205-11.
85. Crabos M, Coste P, Paccalin M et al. Reduced basal NO-mediated dilation and decreased endothelial NO-synthase expression in coronary vessels of spontaneously hypertensive rats. J Mol Cell Cardiol 1997; 29: 55-65.
86. Tojo A, Kimoto M, Wilcox CS. Renal expression of constitutive NOS and DDAH: Separate effects of salt intake and angiotensin. Kidney Int 2000; 58: 2075-83.
87. Ni Z, Vaziri ND. Effect of salt loading on nitric oxide synthase expression in normotensive rats. Am J Hypertens 2001; 14: 155-63.
88. Hirata K, Miki N, Kuroda Y, Sakoda T, Kawashima S, Yokoyama M. Low concentration of oxidized low-density lipoprotein and lysophosphatidylcholine upregulate constitutive nitric oxide synthase mRNA expression in bovine aortic endothelial cells. Circ Res 1995; 76: 958-62.
89. Liao JK, Shin WS, Lee WY, Clark SL. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 1995; 270: 319-24.
90. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: 1129-35.
91. Wallerath T, Witte K, Schäfer SC et al. Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension. Proc Natl Acad Sci U S A 1999; 96: 13 357-62.
92. Yoshizumi M, Perrella MA, Burnett JC, Lee ME. Tumor necrosis factor downregulates an endothelial nitric oxide synthase messenger RNA by shortening its half-life. Circ Res 1993; 73: 205-09.
93. Alonso J, Sanchez De Miguel L, Monton M, Casado S, Ravichandran LV, Johns RA. Up-regulation of endothelial nitric oxide synthase expression by cyclic guanosine 3′,5′-monophosphate. FEBS Lett 1995; 374: 295-98.
94. Belhassen L, Kelly RA, Smith TW, Balligand JL. Nitric oxide synthase (NOS3) and contractile responsiveness to adrenergic and cholinergic agonists in the heart. Regulation of NOS3 transcription in vitro and in vivo by cyclic adenosine monophosphate in rat cardiac myocytes. J Clin Invest 1996; 97: 1908-15.
95. Cosentino F, Hishikawa K, Katusic ZS, Lüscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 1997; 96: 25-28.
96. Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive NOS isoenzymes. Biol Reprod 1999; 61: 1012-18.
97. Yamashita T, Kawashima S, Ozaki M et al. A calcium channel blocker, benidipine, inhibits intimal thickening in the carotid artery of mice by increasing nitric oxide production. J Hypertens 2001; 19: 451-58.
98. Kobayashi N, Yanaka H, Tojo A, Kobayashi K, Matsuoka H. Effects of amlodipine on nitric oxide synthase mRNA expression and coronary microcirculation in prolonged nitric oxide blockade-induced hypertensive rats. J Cardiovasc Pharmacol 1999; 34: 173-81.
99. Escrig A, Marin R, Mas M. Repeated PGE1 treatment enhances nitric oxide and erection responses to nerve stimulation in the rat penis by upregulating constitutive NOS isoforms. J Urol 1999; 162: 2205-10.
100. Abdel-Gawad M, Huynh H, Brock GB. Experimental chronic renal failure-associated erectile dysfunction: Molecular alterations in nitric oxide synthase pathway and IGF-I system. Mol Urol 1999; 3: 117-25.
101. Abdel-Gawad M, Huynh H, Brock GB. The impact of chronic renal failure on nitric oxide synthase isoforms gene expression in the penis and pelvic ganglia of rats. J Urol 1999; 162: 1473-79.
102. Haas CA, Seftel AD, Razmjouei K, Ganz MB, Hampel N, Ferguson K. Erectile dysfunction in aging: Upregulation of endothelial nitric oxide synthase. Urology 1998; 51: 516-22.
103. Zembowicz A, Tang JL, Wu KK. Transcriptional induction of endothelial nitric oxide synthase type III by lysophosphatidylcholine. J Biol Chem 1995; 270: 17 006-10.
104. Colin IM, Kopp P, Zbaren J, Haberli A, Grizzle WE, Jameson JL. Expression of nitric oxide synthase III in human thyroid follicular cells: Evidence for increased expression in hyperthyroidism. Eur J Endocrinol 1997; 136: 649-55.
105. Kobayashi N, Mori Y, Nakano S, Tsubokou Y, Shirataki H, Matsuoka H. Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 2001; 19: 795-801.
106. Fukai T, Siegfried MR, Ushio-Fukai M, Cheng Y, Kojda G, Harrison DG. Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. J Clin Invest 2000; 105: 1631-39.
107. Ennezat PV, Malendowicz SL, Testa M et al. Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes. J Am Coll Cardiol 2001; 38: 194-98.
108. Arnet UA, McMillan A, Dinerman JL, Ballermann B, Lowenstein CJ. Regulation of endothelial nitric-oxide synthase during hypoxia. J Biol Chem 1996; 271: 15 069-73.
109. Phelan MW, Faller DV. Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells. J Cell Physiol 1996; 167: 469-76.
110. Ferrini M, Magee TR, Vernet D, Rajfer J, Gonzalez-Cadavid NF. Aging-related expression of inducible nitric oxide synthase and markers of tissue damage in the rat penis. Biol Reprod 2001; 64: 974-82.
111. Adams MR, Kinlay S, Blake GJ, Orford JL, Ganz P, Selwyn AP. Atherogenic lipids and endothelial dysfunction: Mechanisms in the genesis of ischemic syndromes. Annu Rev Med 2000; 51: 149-67.
112. Davidge ST, Baker PN, McLaughlin MK, Roberts JM. Nitric oxide produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase. Circ Res 1995; 77: 274-83.
113. Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A 1993; 90: 7240-44.
114. Liou JY, Shyue SK, Tsai MJ, Chung CL, Chu KY, Wu KK. Colocalization of prostacyclin synthase with prostaglandin H synthase-1 (PGHS-1) but not phorbol ester-induced PGHS-2 in cultured endothelial cells. J Biol Chem 2000; 275: 15314-20.
115. Vane JR, Mitchell JA, Appleton I et al. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci U S A 1994; 91: 2046-50.
116. Swierkosz TA, Mitchell JA, Warner TD, Botting RM, Vane JR. Co-induction of nitric oxide synthase and cyclooxygenase: Interactions between nitric oxide and prostanoids. Br J Pharmacol 1995; 114: 1335-42.
117. Camacho M, Lopez-Belmonte J, Vila L. Rate of vasoconstrictor prostanoids released by endothelial cells depends on cyclooxygenase-2 expression and prostaglandin I synthase activity. Circ Res 1998; 83: 353-65.
118. Arriero MM, Rodriguez-Feo JA, Celdran A et al. Expression of endothelial nitric oxide synthase in human peritoneal tissue: Regulation by Escherichia coli lipopolysaccharide. J Am Soc Nephrol 2000; 11: 1848-56.
119. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 1997; 100: 2153-57.
120. Ross R. Atherosclerosis - An inflammatory disease. N Engl J Med 1999; 340: 115-25.
121. Maytin M, Leopold J, Loscalzo J. Oxidant stress in the vasculature. Curr Atheroscler Rep 1999; 1: 156-64.
122. Heitzer T, Just H, Münzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 1996; 94: 6-9.
123. Jeremy JY, Angelini GD, Khan M et al. Platelets, oxidant stress and erectile dysfunction: An hypothesis. Cardiovasc Res 2000; 46: 50-54.
124. Murohara T, Kugiyama K, Ohgushi M, Sugiyama S, Yasue H. Cigarette smoke extract contracts isolated porcine coronary arteries by superoxide anion-mediated degradation of EDRF. Am J Physiol 1994; 266: H874-80.
125. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001; 104: 2673-78.
126. Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM. Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 1992; 267: 24173-76.
127. Vasquez-Vivar J, Kalyanaraman B, Martasek P et al. Superoxide generation by endothelial nitric oxide synthase: The influence of co-factors. Proc Natl Acad Sci U S A 1998; 95: 9220-25.
128. Stroes E, Kastelein J, Cosentino F et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 1997; 99: 41-46.
129. Heitzer T, Brockhoff C, Mayer B et al. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: Evidence for a dysfunctional nitric oxide synthase. Circ Res 2000; 86: E36-41.
130. Tiefenbacher CP, Bleeke T, Vahl C, Amann K, Vogt A, Kübler W. Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis. Circulation 2000; 102: 2172-79.
131. Bush PA, Gonzalez NE, Ignarro LJ. Biosynthesis of nitric oxide and citrulline from L-arginine by constitutive nitric oxide synthase present in rabbit corpus cavernosum. Biochem Biophys Res Commun 1992; 186: 308-14.
132. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 2001; 276: 40-47.
133. Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 1986; 320: 454-56.
134. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and the ugly. Am J Physiol Cell Physiol 1996; 271: C1424-37.
135. Zou M, Martin C, Ullrich V. Tyrosine nitration as a mechanism of selective inactivation of prostacyclin synthase by peroxynitrite. Biol Chem 1997; 378: 707-13.
136. MacMillan-Crow LA, Crow JP, Kerby JD, Beckman JS, Thompson JA. Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts. Proc Natl Acad Sci U S A 1996; 93: 11853-58.
137. Sydow K, Böger RH. Homocyst(e)ine, endothelial dysfunction and cardiovascular risk. Pathomechanisms and therapeutical options. Z Kardiol 2001; 90: 1-11.
138. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: A link with cardiovascular disease. J Nutr 2000; 130: 369S-72S.
139. Khan MA, Thompson CS, Emsley AM et al. The interaction of homocysteine and copper markedly inhibits the relaxation of rabbit corpus cavernosum: New risk factors for angiopathic erectile dysfunction? BJU Int 1999; 84: 720-24.
140. Khan MA, Thompson CS, Mumtaz FH et al. The effect of nitric oxide and peroxynitrite on rabbit cavernosal smooth muscle relaxation. World J Urol 2001; 19: 220-24.
141. Cai A, Harrison DG. Endothelial dysfunction in cardiovascular disease. The role of oxidant stress. Circ Res 2000; 87: 840-44.
142. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase. Role in cardiovascular biology and disease. Circ Res 2000; 86: 494-501.
143. Mates JM, Sanchez-Jimenez F. Antioxidant enzymes and their implications in pathophysiologic processes. Front Biosci 1999; 4: D339-45.
144. Stralin P, Karlsson K, Johansson BO, Marklund SL. The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase. Arterioscler Thromb Vasc Biol 1995; 15: 2032-36.
145. Oury TD, Day BJ, Crapo JD. Extracellular superoxide dismutase: A regulator of nitric oxide bioavailability. Lab Invest 1996; 75: 617-36.
146. Stralin P, Marklund SL. Vasoactive factors and growth factors alter vascular smooth muscle cell EC-SOD expression. Am J Physiol Heart Circ Physiol 2001; 281: H1621-29.
147. Fukai T, Siegfried MR, Ushio-Fukai M, Griendling KK, Harrison DG. Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Circ Res 1999; 85: 23-28.
148. Landmesser U, Merten R, Spiekermann S, Büttner K, Drexler H, Hornig B. Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: Relation to endothelium-dependent vasodilation. Circulation 2000; 101: 2264-70.
149. Azadzoi KM, Saenz De Tejada I. Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1991; 146: 238-40.
150. Saenz De Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320: 1025-30.
151. Azadzoi KM, Saenz De Tejada I. Diabetes mellitus impairs neurogenic and endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1992; 148: 1587-91.
152. Khan MA, Thompson CS, Jeremy JY, Mumtaz FH, Mikhailidis P, Morgan RJ. The effect of superoxide dismutase on nitric oxide-mediated and electrical field-stimulated diabetic rabbit cavernosal smooth muscle relaxation. BJU Int 2001; 87: 98-103.
153. Cartledge JJ, Eardley I, Morrison JF. Impairment of corpus cavernosal smooth muscle relaxation by glycosylated human haemoglobin. BJU Int 2000; 85: 735-41.
154. Trigo-Rocha F, Aronson WJ, Hohenfellner M, Ignarro LJ, Rajfer J, Lue TF. Nitric oxide and cGMP: Mediators of pelvic nerve stimulated erection in dogs. Am J Physiol 1993; 264: H419-22.
155. Bush PA, Aronson WJ, Buga GM, Rajfer J, Ignarro LJ. Nitric oxide is a potent relaxant of human and rabbit corpus cavernosum. J Urol 1992; 147: 1650-65.
156. Pickard RS, Powell PH, Zar MA. The effect of inhibitors of nitric oxide biosynthesis and cyclic GMP formation on nerve-evoked relaxation of human cavernosal smooth muscle. Br J Pharmacol 1991; 104: 755-59.
157. G-nitro-L-arginine on the erectile response to cavernous nerve stimulation in the rabbit. Acta Physiol Scand 1991; 143: 299-304.
158. G-nitroarginine inhibits non-adrenergic, non-cholinergic relaxation of human isolated corpus cavernosum. Acta Physiol Scand 1991; 141: 441-42.
159. Faraci FM, Brian JE, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol 1995; 269: H1522-27.
160. Cooke JP, Dzau VJ. Derangements of the nitric oxide synthase pathway, L-arginine, and cardiovascular diseases. Circulation 1997; 96: 379-82.
161. Surdacki A, Nowicki M, Sandmann J et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol 1999; 33: 653-58.
162. Miyazaki H, Matsuoka H, Cooke JP et al. Endogenous nitric oxide synthase inhibitor: A novel marker of atherosclerosis. Circulation 1999; 99: 1141-66.
163. Goonasekera CD, Rees DD, Woolard P, Frend A, Shah V, Dillon MJ. Nitric oxide synthase inhibitors and hypertension in children and adolescents. J Hypertens 1997; 15: 901-909.
164. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; 339: 572-75.
165. MacAllister RJ, Rambausek MH, Vallance P, Williams D, Hoffmann KH, Ritz E. Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure. Nephrol Dial Transplant 1996; 11: 2449-52.
166. G-dimethylarginine in renal insufficiency. Pflugers Arch 2000; 439: 524-31.
167. Schmidt RJ, Domico J, Samsell LS et al. Indices of activity of the nitric oxide system in hemodialysis patients. Am J Kidney Dis 1999; 34: 228-34.
168. Böger RH, Bode-Böger SM. Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases. Semin Thromb Hemost 2000; 26: 539-45.
169. Zoccali C, Benedetto FA, Maas R et al. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol 2002; 13: 490-496.
170. Valkonen VP, Pavia H, Salonen JT et al. Risk of acute coronary events and serum concentrations by asymmetrical dimethylarginine. Lancet 2001; 358: 2127-28.
171. Abbasi F, Asagmi T, Cooke JP et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol 2001; 88: 1201-203.
172. Zoccali C, Bode-Böger S, Mallamaci F et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: A prospective study. Lancet 2001; 358: 2113-17.
173. Bortolotti A, Fedele D, Chatenoud L et al. Cigarette smoking: A risk factor for erectile dysfunction in diabetics. Eur Urol 2001; 40: 392-96.
174. Feldman HA, Johannes CB, Derby CA et al. Erectile dysfunction and coronary risk factors: Prospective results from the Massachusetts male aging study. Prev Med 2000; 30: 328-38.
175. McVary KT, Carrier S, Wessells H. Smoking and erectile dysfunction: Evidence based analysis. J Urol 2001; 166: 1624-32.
176. Leiper J, Vallance P. Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 1999; 43: 542-48.
177. Böger RH, Sydow K, Borlak J et al. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: Involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 2000; 87: 99-105.
178. Fard A, Tuck CH, Donis JA et al. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 2000; 20: 2039-44.
179. Str̈ühlinger MC, Tsao PS, Jeng-Horng H, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway. Role of asymmetric dimethylarginine. Circulation 2001; 104: 2569-75.
180. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: Dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999; 99: 3092-95.
181. G dimethy-L-arginine and their reversibility by vasodilators in conscious rats. Br J Pharmacol 1993; 110: 1457-64.
182. Calver A, Collier J, Leone A, Moncada S, Vallance P. Effect of local intra-arterial asymmetric dimethylarginine (ADAMA) on the forearm arteriolar bed of healthy volunteers. J Hum Hypertens 1993; 7: 193-94.
183. Segarra G, Medina P, Ballester RM et al. Effects of some guanidino compounds on human cerebral arteries. Stroke 1999; 30: 2206-11.
184. Tsikas D, Böger RH, Sandman J, Bode-Böger S, Frölich J. Endogenous nitric oxide synthase inhibitors are responsible for the L-arginine paradox. FEBS Lett 2000; 478: 1-3.
185. Böger RH, Bode-Böger SM. The clinical pharmacology of L-arginine. Annu Rev Pharmacol Toxicol 2001; 41: 79-99.
186. Clarkson P, Adams MR, Powe AJ et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996; 97: 1989-94.
187. Azadzoi KM, Goldstein I, Siroky MB, Traish AM, Krane RJ, Saenz de Tejada I. Mechanisms of ischemia-induced cavernosal smooth muscle relaxation impairment in a rabbit model of vasculogenic erectile dysfunction. J Urol 1998; 150: 2216-22.
188. Chen J, Wollman Y, Cherniochovsky T, Laina A, Sofer M, Matzkin H. Effect of oral administration of high dose nitric oxide donor L-arginine in men with organic erectile dysfunction: Results of a double blind, randomized, placebo controlled study. BJU Int 1999; 83: 267-73.
189. Klotz T, Mahers MJ, Braun M, Bloch W, Engelmann U. Effectiveness of oral L-arginine in first-line treatment of erectile dysfunction in a controlled crossover study. Urol Int 1999; 63: 220-23.
190. Azuma H, Sato J, Hamasaki H, Sagimoto A, Isotani E, Obayashi S. Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of L-arginine in regenerated endothelial cells. Br J Pharmacol 1995; 115: 1001-1004.
191. Edelman ER. On causes: Hippocrates, Aristotle, Robert Koch, and the Dread Pirate Roberts. Circulation 2001; 104: 2509-12.
192. Smith WL, Marnett LJ. Prostaglandin endoperoxide synthase: Structure and catalysis. Biochim Biophys Acta 1991; 1083: 1-17.
193. Urade Y, Watanabe K, Hayaishi O. Prostaglandin D, E, and F synthases. J Lipid Mediat Cell Signal 1995; 12: 257-73.
194. Wang LH, Hajibeigi A, Xu XM, Loose-Mitchell D, Wu KK. Characterization of the promoter of human prostaglandin H synthase-1 gene. Biochem Biophys Res Commun 1993; 190: 406-11.
195. Hirai K, Ezumi Y, Nishida E, Uchiyama T, Takayama H. Comparative study of vanadate- and phorbol ester-induced cyclooxygenase-2 expression in human endothelial cells. Thromb Haemost 1999; 82: 1545-52.
196. Davidge ST. Prostaglandin H synthase and vascular function. Circ Res 2001; 89: 650-60.
197. Smith WL. Prostaglandin biosynthesis and its compartmentation in vascular smooth muscle and endothelial cells. Annu Rev Physiol 1986; 48: 251-62.
198. Toratani A, Sawada S, Kono Y et al. Interleukin-1α stimulated prostacyclin release by increasing gene transcription of prostaglandin H synthase and phospholipase A2 in human vascular endothelial cells. J Cardiovasc Pharmacol 1999; 33: 843-51.
199. Wort SJ, Evans TW. The role of the endothelium in modulating vascular control in sepsis and related conditions. Br Med Bull 1999; 55: 30-48.
200. 2α to regulate prostacyclin synthesis in human endothelial cells. Biochem Biophys Res Commun 2001; 287: 881-87.
201. Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ. Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: Selective upregulation of prostacyclin synthesis by COX-2. J Immunol 2001; 167: 2831-38.
202. Khan MA, Thompson CS, Sullivan ME, Jeremy JY, Mikhailidis DP, Morgan RJ. The role of prostaglandins in the aetiology and treatment of erectile dysfunction. Prostaglandins Leukot Essent Fatty Acids 1999; 60: 169-74.
203. Jeremy JY, Morgan RJ, Mikhailidis DP, Dandona P. Prostacyclin synthesis by the corpora cavernosa of the human penis: Evidence for muscarinic control and pathological implications. Prostaglandins Leukot Med 1986; 23: 211-16.
204. Hedlund H, Andersson KE. Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J Urol 1985; 134: 1245-50.
205. Moncada S. Prostacyclin and artery wall biology. Atherosclerosis 1982; 2: 193-207.
206. 2 in pigtailed monkeys. Int J Impotence Res 1989; 1: 211-21.
207. Traish AM, Moreland RB, Gallant C, Huang YH, Goldstein I. G-protein-coupled receptor agonists augment adenylyl cyclase activity induced by forskolin in human corpus cavernosum smooth muscle cells. Recept Signal Transduct 1997; 7: 121-32.
208. Aboseif S, Riemer RK, Stackl W, Lue T, Tanagho E. Quantification of prostaglandin E1 receptors in cavernous tissue of men, monkeys and dogs. Urol Int 1993; 50: 148-52.
209. Jeremy JY, Mikhailidis DP, Thompson CS, Dandona P. Experimental diabetes mellitus inhibits prostacyclin synthesis by the rat penis: Pathological implications. Diabetologica 1985; 28: 365-68.
210. Sullivan ME, Mikhailidis DP, Thompson CS, Morgan RJ, Angelini GD, Jereny JY. Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the diabetic rabbit. Br J Urol 1998; 82: 578-84.
211. Minhas S, Cartledge JJ, Eardley I, Joyce AD, Morrison JF. The interaction of nitric oxide and prostaglandins in the control of corporal smooth muscle tone: Evidence for production of a cyclooxygenase-derived endothelium-contracting factor. BJU Int 2001; 87: 882-88.
212. Teixeira CE, Moreno RA, Ferreira U et al. Pharmacological characterization of kinin-induced relaxation of human corpus cavernosum. Br J Urol 1998; 81: 432-36.
213. Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P, Dluhy RG. Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum. J Urol 1997; 157: 1920-25.
214. Park JK, Kim SZ, Kim SH, Park YK, Cho KW. Renin angiotensin system in rabbit corpus cavernosum: Functional characterization of angiotensin II receptors. J Urol 1997; 158: 653-58.
215. Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol 1999; 31: 51-60.
216. Timmermans PB, Smith RD. Angiotensin II receptor subtypes: Selective antagonists and functional correlates. Eur Heart J 1994; 15: 79-87.
217. Becker AJ, Ückert S, Stief CG et al. Plasma levels of angiotensin II during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction. Urology 2001; 58: 805-10.
218. Davenport AP. International union of pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev 2002; 54: 219-26.
219. Kedzierski RM, Yanagisawa M. Endothelin system: The double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 2001; 41: 851-76.
220. Fahimi-Vahid M, Gosau N, Michalek C et al. Distinct signaling pathways mediated cardiomyocyte phospholipase D stimulation by endothelin-1 and thrombin. J Mol Cell Cardiol 2002; 34: 441-53.
221. Sirous ZN, Fleming JB, Khalil RA. Endothelin-1 enhances eicosanoids-induced coronary smooth muscle contraction by activating specific protein kinase C isoforms. Hypertension 2001; 37: 497-504.
222. Nakayama K, Ishigai Y, Uchida H, Tanaka Y. Potentiation by endothelin-1 of 5-hydroxytryptamine-induced contraction in coronary artery of the pig. Br J Pharmacol 1991; 104: 978-86.
223. Okatani Y, Taniguchi K, Sagara Y. Amplifying effect of endothelin-1 on serotonin-induced vasoconstriction of human umbilical artery. Am J Obstet Gynecol 1995: 172: 1240-45.
224. 2+]i sensitization pathways. Hypertension 2002; 39: 543-49.
225. Ari G, Vardii Y, Hoffman A, Finberg JP. Possible role for endothelins in penile erection. Eur J Pharmacol 1996; 307: 69-74.
226. Kim NN, Dhir V, Azadzoi KM, Traish AM, Flaherty E, Goldstein I. Pilot study of the endothelin-A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction. J Androl 2002; 23: 76-83.
227. Becker AJ, Ückert S, Stief CG et al. Systemic and cavernous plasma levels of endothelin in healthy males during different functional conditions of the penis. World J Urol 2000; 19: 57-66.
228. Becker AJ, Ückert S, Stief CG, Truss MC, Hartman U, Jonas U. Systemic and cavernous plasma levels of endothelin (1-21) during different penile conditions in healthy males and patients with erectile dysfunction. World J Urol 2001; 19: 267-71.
229. Chilian WM, Koshida R. EDHF and NO: Different pathways for production-similar actions. Circ Res 2001; 89: 648-49.
230. Brandes RP, Schmitz-Winnenthal FH, Feletou M et al. An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice. Proc Natl Acad Sci U S A 2000; 97: 9747-52.