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Horm Metab Res 2004; 36(5): 319-335
DOI: 10.1055/s-2004-814489
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

The Role of Nitric Oxide in the Development of Diabetic Angiopathy

F.  Santilli1 , F.  Cipollone1 , A.  Mezzetti1 , F.  Chiarelli1
  • 1Departments of Medicine and Pediatrics, University of Chieti, Italy
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Publikationsverlauf

Received 9 April 2003

Accepted after Revision 3 December 2003

Publikationsdatum:
24. Mai 2004 (online)

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Abstract

Diabetic angiopathy is the main cause of morbidity and mortality in patients with diabetes mellitus. Clinical manifestations and pathophysiological mechanisms of diabetic angiopathy can be traced back to the development of endothelial cell dysfunction with alterations in the eNOS/NO system production or availability as the primum movens in its natural history. Hyperglycemia per se or through the accumulation of AGEs, increased oxidative stress, leading to NOS uncoupling and NO-quenching by excess superoxide and peroxynitrite, and individual genetic background are thought to be responsible for this NO metabolism imbalance. The complex interplay of these mechanisms results in a perturbation of the physiological properties of NO in the maintenance of endothelial homeostasis, such as vasodilation, anticoagulation, leukocyte adhesion, smooth muscle cell proliferation, and antioxidant capacity. Hence, abnormality in NO availability results in generalized accelerated atherosclerosis, hyperfiltration, glomerulosclerosis, tubulointerstitial fibrosis and progressive decline in glomerular filtration rate, and apoptosis and neovascularization in the retina. Indeed, the parallel development of nephropathy, retinopathy, and macroangiopathy may be considered as manifestations of endothelial dysfunction at distinct vascular sites. Given this scenario, intervention targeting any of the pathways involved in the NOS/NO system cascade may prove potential therapeutic targets in the prevention of long-term diabetic complications.

Key words

Diabetes - Nephropathy - Retinopathy - Macroangiopathy - Endothelial dysfunction

References

  • 1 Head J, Fuller J H. International variations in mortality among diabetic patients: the WHO Multinational Study of Vascular disease in diabetics.  Diabetologia. 1990;  24 336-341
    PubMedGoogle Scholar
  • 2 Dorman J S, Laporte R E, Kuller L H, Cruickshanks K J, Orchard T J, Wagener D K, Becker D J, Cavender D E, Drash A L. The Pittsburgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study. Mortality results.  Diabetes. 1984;  33 271-276
    CrossrefPubMedGoogle Scholar
  • 3 Stehouwer C DA, Lambert J, Donker A JM, van Hinsbergh V WM. Endothelial dysfunction and pathogenesis of diabetic angiopathy.  Cardiovasc Res. 1997;  34 55-68
    CrossrefPubMedGoogle Scholar
  • 4 Reddy K G, Nair R, Sheehan H, Hodgson J. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis.  J Am Coll Cardiol. 1994;  23 833- 843
    PubMedGoogle Scholar
  • 5 Quyiumi A A, Dakak N, Andrews N, Hussain S, Arora S, Gilligan D, Panza J A. Nitric oxide activity in the human coronary circulation: impact of risk factors for coronary atherosclerosis.  J Clin Invest. 1995;  95 1747-1753
    PubMedGoogle Scholar
  • 6 Dzau V J, Gibbons G H, Mann M, Braun-Dullaeus R. Future horizons in cardiovascular molecular therapies.  Am J Cardiol. 1997;  80 (9A) 33-39
    PubMedGoogle Scholar
  • 7 Bell D, Johns T E, Lopez L M. Endothelial dysfunction: implications for therapy of cardiovascular diseases.  Ann Pharmacother. 1998;  32 459-470
    PubMedGoogle Scholar
  • 8 Ludmer P L, Selwyn A P, Shook L T, Wayne R R, Mudge G H, Alexander R W, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.  N Engl J Med. 1986;  315 1046 -1051
    CrossrefPubMedGoogle Scholar
  • 9 Moncada S, Palmer R M, Higgs E A. Nitric oxide: physiology, pathophysiology, and pharmacology.  Pharmacol Rev. 1991;  43 109-142
    PubMedGoogle Scholar
  • 10 Leibovich S J, Polverini P J, Fong T W, Harlow L A, Koch A E. Production of angiogenic activity by human monocytes requires an L-arginine/nitric oxide-synthase-dependent effector mechanism.  Proc Natl Acad Sci USA. 1994;  91 4190-4194
    PubMedGoogle Scholar
  • 11 Kubes P, Suzuki M, Granger D N. Nitric oxide: an endogenous modulator of leukocyte adhesion.  Proc Natl Acad Sci USA. 1991;  88 4651- 4655
    CrossrefPubMedGoogle Scholar
  • 12 Niu X, Smith C W, Kubes P. Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils.  Circ Res. 1994;  74 1133-1140
    PubMedGoogle Scholar
  • 13 Dubey R, Jackson E, Luscher T F. Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cells.  J Clin Invest. 1995;  96 141-149
    PubMedGoogle Scholar
  • 14 Garg U C, Hassid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells.  J Clin Invest. 1989;  83 1774-1777
    CrossrefPubMedGoogle Scholar
  • 15 Von der Leyen H, Gibbons G, Morishita R, Lewis N, Zhang L, Nakajima M, Kaneda Y, Cooke J, Dzau V J. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene.  Proc Natl Acad Sci USA. 1995;  92 1137-1141
    CrossrefPubMedGoogle Scholar
  • 16 Cines D B, Pollak E, Buck C A, Loscalzo J, Zimmerman G A, McEver R P, Pober J S, Wick T M, Konkle B A, Schwartz B S, Barnathan E S, McCrae K R, Hug B A, Schmidt A-M, Stern D M. Endothelial cell in physiology and in the pathophysiology of vascular disorders.  Blood. 1998;  91 3527-3561
    PubMedGoogle Scholar
  • 17 Kanner J, Harel S, Granit R. Nitric oxide as an antioxidant.  Arc Biochem Biophys. 1991;  289 130-136
    PubMedGoogle Scholar
  • 18 Griffith T M, Edwards D H, Lewis M G, Newby A C, Henderson A H. The nature of endothelium-derived vascular relaxant factor.  Nature. 1984;  308 645-647
    CrossrefPubMedGoogle Scholar
  • 19 Poston L, Taylor P D. Endothelium-mediated vascular function in insulin-dependent diabetes mellitus.  Clin Sci. 1995;  3 245-255
    PubMedGoogle Scholar
  • 20 Huvers F C, de Leeuw P W, Houben A J, de Haan C H, Hamulyak K, Schouten H, Wolffenbuttel B H, Schaper N C. Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under near-normoglycemic conditions.  Diabetes. 1999;  48 1300-1307
    PubMedGoogle Scholar
  • 21 Johnstone M T, Creager S J, Scales K M, Cusco J A, Lee B K, Creager M A. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.  Circulation. 1993;  88 2510-2516
    PubMedGoogle Scholar
  • 22 Lambert J, Aarsen M, Donker A J, Stehouwer C D. Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus.  Arterioscler Thromb Vasc Biol. 1996;  16 705-711
    PubMedGoogle Scholar
  • 23 Morris B J, Markus A, Glenn C L, Adams D J, Colagiuri D, Wang L. Association of a functional inducible nitric oxide synthase promoter variant with complications in type 2 diabetes.  J Mol Med. 2002;  80 96-104
    CrossrefPubMedGoogle Scholar
  • 24 Steinberg H O, Brechtel G, Johnson A, Fineberg N, Baron A D. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.  J Clin Invest. 1994;  94 1172-1179
    CrossrefPubMedGoogle Scholar
  • 25 Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin’s vascular effects in humans.  J Clin Invest. 1994;  94 2511-2515
    CrossrefPubMedGoogle Scholar
  • 26 Grover A, Padginton C, Wilson M F, Sung B H, Izzo J L Jr, Dandona P. Insulin attenuates norepinephrine-induced venoconstriction. An Ultrasonographic Study.  Hypertension. 1995;  25 779-784
    PubMedGoogle Scholar
  • 27 Zeng G, Quon M J. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurements in vascular endothelial cells.  J Clin Invest. 1996;  98 894-898
    CrossrefPubMedGoogle Scholar
  • 28 Aljada A, Dandona P. Effect of insulin on human aortic endothelial nitric oxide synthase.  Metabolism. 2000;  49 147-150
    CrossrefPubMedGoogle Scholar
  • 29 Laakso M, Edelman S V, Brechtel G, Baron A D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance.  J Clin Invest. 1990;  85 1844-1852
    CrossrefPubMedGoogle Scholar
  • 30 Laakso M, Edelman S V, Brechtel G, Baron A D. Impaired insulin-mediated skeletal muscle bloodflow in patients with NIDDM.  Diabetes. 1992;  41 1076-1083
    CrossrefPubMedGoogle Scholar
  • 31 Baron A D, Brechtel-Hook G, Johnson A, Hardin D. Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure.  Hypertension. 1993;  21 129-135
    PubMedGoogle Scholar
  • 32 Baron A D, Brechtel G. Insulin differentially regulates systemic and skeletal muscle vascular resistance.  Am J Physiol. 1993;  265 E61-E67
    PubMedGoogle Scholar
  • 33 Zeng G, Nystrom F H, Ravichandran L V, Cong L N, Kirby M, Mostowski H, Quon M. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells.  Circulation. 2000;  101 1539-1545
    CrossrefPubMedGoogle Scholar
  • 34 Kuboki K, Jiang Z Y, Takahara N, Ha S W, Igarashi M, Yamauchi T, Feener E P, Herbert T P, Rhodes C J, King G L. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin.  Circulation. 2000;  101 676-681
    PubMedGoogle Scholar
  • 35 Weisbrod R M, Brown M L, Cohen R A. Effect of elevated glucose on cyclic GMP and eicosanoid produced by porcine aortic endothelium.  Arterioscler. Thromb1993;  13 915-923
    PubMedGoogle Scholar
  • 36 Giugliano D, Marfella R, Coppola L, Verazzo G, Acampora R, Giunta R, Nappo F, Lucarelli C, D’Onofrio F. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine: evidence for reduced availability of nitric oxide during hyperglycemia.  Circulation. 1997;  95 1783-1790
    CrossrefPubMedGoogle Scholar
  • 37 Bucala R, Trace Y KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes.  J Clin Invest. 1991;  87 432- 438
    CrossrefPubMedGoogle Scholar
  • 38 Kojda G, Harrison D. Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure.  Cardiovasc Res. 1999;  43 562-571
    CrossrefPubMedGoogle Scholar
  • 39 Cai H, Harrison D G. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress.  Circ Res. 2000;  87 840-844
    CrossrefPubMedGoogle Scholar
  • 40 Thomson L, Trujillo M, Telleri R, Radi R. Kinetics of cytochrome c21 oxidation by peroxynitrite: implications for superoxide measurements in nitric oxide-producing biological systems.  Arch Biochem Biophys. 1995;  319 491- 497
    CrossrefPubMedGoogle Scholar
  • 41 Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl R A, Warnholtz A, Meinertz T, Griendling K, Harrison D G, Forstermann U, Munzel T. Mechanisms underlying endothelial dysfunction in diabetes mellitus.  Circ Res. 2001;  88 e14-e22
    PubMedGoogle Scholar
  • 42 Shinozaki K, Kashiwagi A, Nishio Y, Okamura T, Yoshida Y, Masada M, Toda N, Kikkawa R. Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2-imbalance in insulin-resistant rat aorta.  Diabetes. 1999;  48 2437-2445
    CrossrefPubMedGoogle Scholar
  • 43 Pieper G M. Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin.  J Cardiovasc Pharmacol. 1997;  29 8-15
    CrossrefPubMedGoogle Scholar
  • 44 Meininger C J, Marinos R S, Hatakeyama K, Martinez-Zaguilan R, Rojas J D, Kelly K A, Wu G. Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency.  Biochem J. 2000;  349 353-356
    CrossrefPubMedGoogle Scholar
  • 45 Munzel T, Li H, Mollnau H, Hink U, Matheis E, Hartmann M, Oelze M, Skatchkov M, Warnholtz A, Duncker L, Meinertz T, Forstermann U. Effects of long-term nitroglycerin treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS III-mediated superoxide production, and vascular NO bioavailability.  Circ Res. 2000;  86 e7-e12
    PubMedGoogle Scholar
  • 46 Cosentino F, Hishikawa K, Katusic Z S, Luscher T F. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells.  Circulation. 1997;  96 25-28
    PubMedGoogle Scholar
  • 47 Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P. Glucose challenge stimulates reactive oxygen species (ROS) generation by leukocytes.  J Clin Endocrinol Metab. 2000;  85 2970-2973
    CrossrefPubMedGoogle Scholar
  • 48 Mohanty P, Ghanim H, Hamouda W, Aljada A, Garg R, Dandona P. Both lipid and protein intake stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells.  Am J Clin Nutr. 2002;  75 767-772
    PubMedGoogle Scholar
  • 49 Milson A B, Jones C J, Goodfellow J, Frenneaux M P, Peters J R, James P E. Abnormal metabolic fate of nitric oxide in type 1 diabetes mellitus.  Diabetologia. 2002;  45 1515-1522
    CrossrefPubMedGoogle Scholar
  • 50 Ruggenenti P, Remuzzi G. Nephropathy of type-2-diabetes mellitus.  J Am Soc Nephrol. 1998;  9 2157-2169
    PubMedGoogle Scholar
  • 51 Mogensen C E. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas.  Diabetologia. 1999;  42 263-285
    CrossrefPubMedGoogle Scholar
  • 52 Adler S. Structure-function relationships associated with extracellular matrix alterations in diabetic glomerulopathy.  J Am Soc Nephrol. 1994;  5 1165-1172
    PubMedGoogle Scholar
  • 53 Ziyadeh F N. Significance of tubulointerstitial changes in diabetic renal disease.  Kidney Int. 1996;  54 10 -13
    PubMedGoogle Scholar
  • 54 Deckert T, Yokoyama H, Mathiesen E, Ronn B, Jensen T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen J S. Cohort study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in patients with insulin dependent diabetes.  BMJ. 1996;  312 871-874
    PubMedGoogle Scholar
  • 55 Deckert T, Poulsen J E, Larsen M. Prognosis of diabetics with diabetes onset before the age of 31: survival, causes of death and complications.  Diabetologia. 1978;  14 363-370
    CrossrefPubMedGoogle Scholar
  • 56 The DCCT Research Group . The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus: the Diabetes Control and Complications Trial.  N Engl J Med. 1993;  329 977-986
    Google Scholar
  • 57 Corbett J A, Tilton R G, Chang K, Hassan K S, Ido Y, Wang J L, Sweetland M A, Lancaster J R, Williamson J R, McDaniel M L. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction.  Diabetes. 1992;  41 552-556
    PubMedGoogle Scholar
  • 58 Graier W F, Wascher T C, Lackner L, Toplak H, Krejs G J, Kukovetz W R. Exposure to elevated D-glucose concentrations modulates vascular endothelial cell vasodilatory response.  Diabetes. 1993;  42 1497-1505
    PubMedGoogle Scholar
  • 59 Pugliese G, Tilton R G, Williamson J R. Glucose-induced metabolic imbalances in the pathogenesis of diabetic vascular disease.  Diabetes Metab Rev. 1991;  7 35-59
    CrossrefPubMedGoogle Scholar
  • 60 Tolins P, Shultz P J, Raij L, Brown D M, Mauer S M. Abnormal renal hemodynamic response to reduced renal perfusion in diabetic rats: role of NO.  Am J Physiol. 1993;  265 F886-F895
    PubMedGoogle Scholar
  • 61 Reyes A A, Karl I E, Kissane J, Klahr S. L-arginine administration prevents glomerular hyperfiltration and decreases proteinuria in diabetic rats.  J Am Soc Nephrol. 1993;  4 1039-1045
    PubMedGoogle Scholar
  • 62 Bank N, Aynedjian H S. Role of EDRF (nitric oxide) in diabetic renal hyper-filtration.  Kidney Int. 1993;  43 1306-1312
    PubMedGoogle Scholar
  • 63 Tolins J P, Palmer R MJ, Moncada S, Raij L. Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses.  Am J Physiol. 1990;  258 H655-H662
    PubMedGoogle Scholar
  • 64 Nathan C, Xie Q W. Regulation of biosynthesis of nitric oxide.  J Biol Chem. 1994;  269 13 725-13 728
    PubMedGoogle Scholar
  • 65 Kone B C, Baylis C. Biosynthesis and homeostatic roles of nitric oxide in the normal kidney.  Am J Physiol. 1997;  272 F561-F578
    PubMedGoogle Scholar
  • 66 Choi K C, Kim N H, An M R, Kang D G, Kim S W, Lee J. Alterations of intrarenal renin-angiotensin and nitric oxide systems in streptozotocin-induced diabetic rats.  Kidney Int Suppl. 1997;  60 S23-S27
    PubMedGoogle Scholar
  • 67 Ishii N, Patel K P, Lane P H, Taylor T, Bian K, Murad F, Pollock J S, Carmines P K. Nitric oxide synthesis and oxidative stress in the renal cortex of rats with diabetes mellitus.  J Am Soc Nephrol. 2001;  12 1630-1639
    PubMedGoogle Scholar
  • 68 Schwartz D, Schwartz I F, Blantz R C. An analysis of renal nitric oxide contribution to hyperfiltration in diabetic rats.  J Lab Clin Med. 2001;  137 107-114
    CrossrefPubMedGoogle Scholar
  • 69 Sugimoto H, Shikata K, Wada J, Horiuchi S, Makino H. Advanced glycation end-products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-alpha and inducible nitric oxide sinthase in diabetic rat glomeruli.  Diabetologia. 1999;  42 878-886
    CrossrefPubMedGoogle Scholar
  • 70 Veelken R, Hilgers K F, Hartner A. Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy.  J Am Soc Nephrol. 2000;  11 71-79
    PubMedGoogle Scholar
  • 71 Trachtman H, Futterweit S, Pine E, Mann J, Valderrama E. Chronic diabetic nephropathy: role of inducible nitric oxide synthase.  Pediatric Nephrol. 2002;  17 20-29
    CrossrefPubMedGoogle Scholar
  • 72 Noh H, Ha H, Yu M R, Kang S W, Choi K H, Han D S, Lee H Y. High glucose increases inducible NO production in cultured rat mesangial cells. Possible role in fibronectin production.  Nephron. 2002;  90 78-85
    CrossrefPubMedGoogle Scholar
  • 73 Sugimoto H, Shikata K, Matsuda M, Hayashi Y, Hiragushi K, Wada J, Makino H. Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy.  Diabetologia. 1998;  41 1426-1434
    CrossrefPubMedGoogle Scholar
  • 74 Komers R, Allen T J, Cooper M E. Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes.  Diabetes. 1994;  43 1190-1197
    PubMedGoogle Scholar
  • 75 Tilton R G, Ghang K, Hasan K S, Smith S R, Petrash J M, Misko T P, Moore W M, Currie M G, Corbett J A, McDaniel M L, Williamson J R. Prevention of diabetic vascular dysfunction by guanidines: inhibition of nitric oxide synthase vs. advanced glycation end-product formation.  Diabetes. 1993;  42 221-232
    PubMedGoogle Scholar
  • 76 Pieper G M, Dembdy K, Siebeneich W. Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction.  Diabetologia. 1998;  41 1220-1226
    CrossrefPubMedGoogle Scholar
  • 77 Mattar A L, Fujihara C K, Ribeiro M O, de Nucci G, Zatz R. Renal effects of acute and chronic nitric oxide inhibition in experimental diabetes.  Nephron. 1996;  74 136-143
    PubMedGoogle Scholar
  • 78 De Vriese A S, Stoenoiu M S, Elger M, Devuyst O, Vanholder R, Kriz W, Lameire N H. Diabetes-induced microvascular dysfunction in the hydronephrotic kidney: role of nitric oxide.  Kidney Int. 2001;  60 202-210
    CrossrefPubMedGoogle Scholar
  • 79 Hiragushi K, Sugimoto H, Shikata K, Yamashita T, Miyatake N, Hikata Y, Wada J, Kumagai I, Fukushima M, Makino H. Nitric oxide system is involved in glomerular hyperfiltration in Japanese normo- and microalbuminuric patients with type 2 diabetes.  Diabetes Res Clin Pract. 2001;  53 149-159
    CrossrefPubMedGoogle Scholar
  • 80 Marletta M A, Yoon P S, Iyengar R, Leaf C D, Wishnok J S. Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate.  Biochemistry. 1988;  27 8706-8711
    CrossrefPubMedGoogle Scholar
  • 81 Rosselli M, Imthurn B, Keller P J, Jackson E K, Dubey R K. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17-estradiol and norethisterone acetate.  Hypertension. 1995;  25 (Part 2) 848-853
    PubMedGoogle Scholar
  • 82 Chiarelli F, Cipollone F, Romano F, Tumini S, Costantini F, di Ricco L, Pomilio M, Pierdomenico S D, Marini M, Cuccurullo F, Mezzetti A. Increased circulating nitric oxide in young patients with type 1 diabetes and persistent microalbuninuria.  Diabetes. 2000;  49 1258-1263
    PubMedGoogle Scholar
  • 83 Noh H, Ha H, Yu M R, Kang S W, Choi K H, Han D S, Lee H Y. High glucose increases inducible NO production in cultured rat mesangial cells. Possible role in fibronectin production.  Nephron. 2002;  90 78-85
    CrossrefPubMedGoogle Scholar
  • 84 Tilton R G, Chang K C, Lejeune W S, Stephan C C, Brock T A, Williamson J R. Role of nitric oxide in the hyperpermeability and haemodinamic changes induced by intravenous VEGF.  Invest Ophthalmol Vis Sci. 1999;  40 689-696
    PubMedGoogle Scholar
  • 85 Cooper M E, Vranes D, Youssef S, Stacker S A, Cox A J, Rizkalla B, Casley D J, Bach L A, Kelly D J, Gilbert R E. Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes.  Diabetes. 1999;  42 579-588
    PubMedGoogle Scholar
  • 86 De Vriese A S, Tilton R G, Elger M, Stephan C C, Kriz W, Lameire N H. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes.  J Am Soc Nephrol.. 2001;  12 993-1000
    PubMedGoogle Scholar
  • 87 Craven P A, Studer R K, DeRubertis F R. Impaired NO - dependent cyclic GMP generation in glomeruli from diabetic rats: Evidence for protein kinase C-mediated suppression of the cholinergic response.  J Clin Invest. 1994;  93 311-320
    PubMedGoogle Scholar
  • 88 Craven P A, Studer R K, DeRubertis F R. Impaired nitric oxide release by glomeruli from diabetic rats.  Metabolism. 1995;  44 695-698
    CrossrefPubMedGoogle Scholar
  • 89 Mc Veigh G E, Brennan G M, Johnstone G D, Mc Dermott B J, Mc Grath L T, Henry W R, Andrews J W, Hayes J R. Impaired endothelium-dependent vasodilation in patients with type 2 diabetes mellitus.  Diabetologia. 1992;  35 771-776
    PubMedGoogle Scholar
  • 90 Tesfamariam B, Cohen R A. Free radicals mediate endothelial cell dysfunction caused by elevated glucose.  Am J Physiol. 1992;  263 H321-H326
    PubMedGoogle Scholar
  • 91 Schnackenberg C G, Welch W J, Wilcox C S. TP receptor-mediated vasoconstriction in microperfused afferent arterioles: roles of O2- and NO.  Am J Physiol Renal Physiol. 2000;  279 F302- F308
    PubMedGoogle Scholar
  • 92 Ohishi K, Carmines P K. Superoxide dismutase restores the influence of nitric oxide on renal arterioles in diabetes mellitus.  J Am Soc Nephrol. 1995;  5 1559-1566
    PubMedGoogle Scholar
  • 93 Dai F, Diederich A, Skopec J, Diederich D. Diabetes-induced endothelial dysfunction in streptozotocin-treated rats: role of prostaglandin endoperoxides and free radicals.  J Am Soc Nephrol. 1993;  4 1327-1336
    PubMedGoogle Scholar
  • 94 Schoonmaker G C, Fallet R W, Carmines P K. Superoxide anion curbs nitric oxide modulation of afferent arteriolar Ang II responsiveness in diabetes mellitus.  Am J Physiol Renal Physiol. 2000;  278 F302-F309
    PubMedGoogle Scholar
  • 95 Eddy A A. Molecular insights into renal interstitial fibrosis.  J Am Soc Nephrol. 1996;  7 2495-2508
    PubMedGoogle Scholar
  • 96 Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage.  J Clin Invest. 1992;  90 278-281
    CrossrefPubMedGoogle Scholar
  • 97 Fujihara C K, Denucci G, Zatz R. Chronic nitric oxide synthesis inhibition aggravates glomerular injury in rats with subtotal nephrectomy.  J Am Soc Nephrol. 1995;  5 1498-1507
    PubMedGoogle Scholar
  • 98 MacKay K, Kondaiah P, Danielpour D, Austin H A III, Brown P D. Expression of transforming growth factor ß1 and ß2 in rat glomeruli.  Kidney Int. 1990;  38 1095-1100
    PubMedGoogle Scholar
  • 99 Studer R K, DeRubertis F R, Craven P A. Nitric oxide suppresses increases in mesangial cell protein kinase C, transforming growth factor ß and fibronectin synthesis induced by thromboxane.  J Am Soc Nephrol. 1996;  7 999-1005
    PubMedGoogle Scholar
  • 100 Baylis C, Harvey J, Engels K. Acute nitric oxide blockade amplifies the renal vasoconstrictor actions of angiotensin II.  J Am Soc Nephrol. 1994;  5 211-214
    PubMedGoogle Scholar
  • 101 Kubes P, Granger D N. Nitric oxide modulates vascular permeability.  Am J Physiol. 1992;  262 H611-H615
    PubMedGoogle Scholar
  • 102 Witte M B, Kiyama T, Barbul A. Nitric oxide enhances experimental wound healing in diabetes.  Br J Surg. 2002;  89 1594-601
    CrossrefPubMedGoogle Scholar
  • 103 Clancy R M, Leszczynska P, Piziak J, Abramson S B. Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on NADPH oxidase.  J Clin Invest. 1992;  90 1116-1121
    PubMedGoogle Scholar
  • 104 Hogg N, Kalyanaraman B, Josef J, Struck A, Parthasarathy S. Inhibition of low density lipoprotein oxidation by nitric oxide. Potential role in atherogenesis.  FEBS Lett. 1993;  34 170-174
    PubMedGoogle Scholar
  • 105 Kourembanas S, McQuillan L P, Leung G K, Faller D V. Nitric oxide regulates the expression of vasocontrictors and growth factors by vascular endothelium under both normoxia and hypoxia.  J Clin Invest. 1993;  92 99-104
    PubMedGoogle Scholar
  • 106 Kaikita K, Fogo A B, Ma L, Schoenhard J A, Brown N J, Vaughan D E. Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition.  Circulation . 2001;  104 839-44
    CrossrefPubMedGoogle Scholar
  • 107 Neugebauer S, Baba T, Watanabe T. Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes.  Diabetes. 2000;  49 500-503
    CrossrefPubMedGoogle Scholar
  • 108 Johannesen J, Tarnow L, Parving H H, Nerup J, Pociot F. CCTTT-repeat polymorphism in the human NOS2-promoter confers low risk of diabetic nephropathy in type 1 diabetic patients.  Diabetes Care. 2000;  19 560-562
    PubMedGoogle Scholar
  • 109 Tsukada T, Yokoyama K, Arai T, Takemoto F, Hara S, Yamada A, Kawaguchi Y, Hosoya T, Igarashi J. Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in human.  Biochem Biophys Res Commun. 1998;  245 190-193
    CrossrefPubMedGoogle Scholar
  • 110 Taniwaki H, Ishimura E, Matsumoto N, Emoto M, Inaba M, Nishizawa Y. Relation between ACE gene and ecNOS gene polimorphisms and resistive index in type 2 diabetic patients with nephropathy.  Diabetes Care. 2001;  24 1653-1660
    PubMedGoogle Scholar
  • 111 Marsden P A, Heng H HQ, Scherer S W, Stewart R J, Hall A V, Shi X M, Tsui L C, Schappert K T. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene.  J Biol Chem. 1993;  268 17 478-17 488
    PubMedGoogle Scholar
  • 112 Graham A, Heath P, Morten J EN, Markham A F. The human aldose reductase gene maps to region 7q35.  Hum Genet. 1991;  86 509-514
    PubMedGoogle Scholar
  • 113 Heesom A E, Hibberd M L, Millward A, Demaine A G. Polymorphism in the 5-end of the aldose reductase gene is strongly associated with the development of diabetic nephropathy in type I diabetes.  Diabetes. 1997;  46 287-291
    PubMedGoogle Scholar
  • 114 Bonner T I, Modi W S, Seuanez H N, O’Brien S J. Chromosomal mapping of five human genes encoding muscarinic acetylcholine receptors.  Cytogenet Cell Genet. 1991;  58 1850-1851
    PubMedGoogle Scholar
  • 115 Merimee T J. Diabetic retinopathy. A synthesis of perspectives.  N Engl J Med. 1990;  322 978-983
    PubMedGoogle Scholar
  • 116 Frank R N. Diabetic retinopathy.  Prog Retin Eye Res. 1995;  14 361-393
    CrossrefPubMedGoogle Scholar
  • 117 Becquet F, Courtois Y, Goureau O. Nitric oxide in the eye: multifaceted roles and diverse outcomes.  Surv Ophthalmol. 1997;  42 71-82
    PubMedGoogle Scholar
  • 118 Yoshida A, Pozdnyakov N, Dang L, Orselli S M, Reddy V N, Sitaramayya A. Nitric oxide synthesis in retinal photoreceptor cells.  Vis Neurosci. 1995;  12 493-500
    PubMedGoogle Scholar
  • 119 Chakravarthy U, Stitt A W, McNally J. Nitric oxide synthase activity and expression on retinal capillary endothelial cells and pericytes.  Curr Eye Res. 1995;  14 285-294
    PubMedGoogle Scholar
  • 120 Goureau O, Hicks D, Courtois Y. Nitric oxide decreases in vivo phagocytosis of photoreceptor outer segments by bovine retina pigmented epithelial cells.  J Cell Physiol. 1994;  159 259-262
    PubMedGoogle Scholar
  • 121 Dighiero P, Reux I, Hauw J J, Fillet A M, Courtois Y, Goureau O. Expression of inducible nitric oxide synthase in cytomegalovirus-infected glial cells of retinas from AIDS patients.  Neurosci Lett. 1994;  166 31-34
    CrossrefPubMedGoogle Scholar
  • 122 Goureau O, Bellot J, Thillage B, Courtois Y, de Kozak Y. increased nitric oxide production in endotoxin-induced uveitis.  J Immunol. 1995;  154 6518-6523
    PubMedGoogle Scholar
  • 123 EL-Asrar A MA, Desmet S, Meersschaert A, Dralands L, Missotten L, Geboes K. Expression of the inducible isoform of nitric oxide synthase in the retinas of human subjects with diabetes mellitus.  Am J Ophthalmol. 2001;  132 551-556
    CrossrefPubMedGoogle Scholar
  • 124 Hattenbach L o, Allers A, Klais C, Koch F, Hecker M. L-Arginine-nitric oxide pathway-related metabolites in the aqueous humor of diabetic patients.  Invest Ophthalmol Vis Sci. 2000;  41 213-217
    PubMedGoogle Scholar
  • 125 Yilmaz G, Esser P, Kociek N, Aydin P, Heimann K. Elevated vitreous nitric oxide levels in patients with proliferative diabetic retinopathy.  Am J Ophthalmol. 2000;  130 87-90
    CrossrefPubMedGoogle Scholar
  • 126 Shibuki H, Katai N, Yodoi J, Uchida K, Yoshimura N. Lipid peroxidation and peroxynitrite in retinal ischemia-reperfusion injury.  Invest Ophthalmol Vis Sci. 2000;  19 3607-3614
    PubMedGoogle Scholar
  • 127 Sugimoto H, Shikata K, Matsuda M, Kushiro M, Hayashi Y, Hiragushi K, Wada J, Makino H. Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy.  Diabetologia. 1998;  19 1426-1434
    PubMedGoogle Scholar
  • 128 Hartnett M E, Stratton R D, Browne R W, Rosner B A, Lanham R J, Armstrong D. Serum markers of oxidative stress and severity of diabetic retinopathy.  Diabetes Care. 2000;  19 234-240
    PubMedGoogle Scholar
  • 129 Goureau O, Hicks D, Courtois Y. Human retina pigment epithelial cells produce nitric oxide in response to cytokines.  Biochem Biophys Res Comm. 1994;  198 120-126
    CrossrefPubMedGoogle Scholar
  • 130 Ziche M, Morbidelli L, Masini E, Amerini S, Granger H J, Maggi C A, Geppetti P, Ledda F. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P.  J Clin Invest. 1994;  94 2036-2044
    PubMedGoogle Scholar
  • 131 Aiello L P, Wong J S. Role of vascular endothelial growth factor in diabetic vascular complications.  Kidney Int. 2000;  19 S113-119
    PubMedGoogle Scholar
  • 132 Tilton R G, Chang K C, LeJeune W S, Stephan C C, Brock T A, Williamson J R. Role for nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGF.  Invest Ophthalmol Vis Sci. 1999;  19 689-696
    PubMedGoogle Scholar
  • 133 Papapetropoulos A, Garcia-Cardenya G, Madri J A, Sessa W C. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells.  J Clin Invest. 1997;  19 3131-3139
    PubMedGoogle Scholar
  • 134 Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun C O, Buerk D G, Huang P L, Jain R K. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability.  Proc Natl Acad Sci USA. 2001;  19 2604-2609
    PubMedGoogle Scholar
  • 135 Brooks S E, Gu X, Samuel S, Marcus D M, Bartoli M, Huang P L, Caldwell R B. Reduced severity of oxygen-induced retinopathy in eNOS-deficient mice.  Invest Ophthalmol Vis Sci. 2001;  19 222-228
    PubMedGoogle Scholar
  • 136 Sennlaub F, Courtois Y, Goureau O. Inducible nitric oxide synthase mediates the change from retinal to vitreal neovascularization in ischemic retinopathy.  J Clin Invest. 2001;  19 717-725
    PubMedGoogle Scholar
  • 137 Hernandez C, Lecube A, Segura R M, Sararols L, Simo R. Nitric oxide and vascular endothelial growth factor concentrations are increased but not related in vitreous fluid of patients with proliferative diabetic retinopathy.  Diabet Med. 2002;  19 655-60
    CrossrefPubMedGoogle Scholar
  • 138 Bek T. Transretinal histopathological changes in capillary-free areas of diabetic retinopathy.  Acta Ophthalmol. 1994;  72 409-415
    PubMedGoogle Scholar
  • 139 Palmowski A M, Sutter E E, Bearse Jr M A, Fung W. Mapping of retinal function in diabetic retinopathy using the multifocal electroretinogram.  Invest Opthalmol Vis Sci. 1997;  38 2586-2596
    PubMedGoogle Scholar
  • 140 Brune B, von Knethen A, Sandau K B. Nitric oxide and its role in apoptosis.  Eur J Pharmacol. 1998;  351 261-272
    CrossrefPubMedGoogle Scholar
  • 141 Yamakura F, Taka H, Fujimura T, Murayama K. Inactivation of human manganese-superoxide dismutase by peroxynitrate is caused by exclusive nitration of tyrosine 34 to 3-nitrotyrosine.  J Biol Chem. 1998;  273 14 085-14 089
    PubMedGoogle Scholar
  • 142 Mac Millan-Crow L A, Thompson A. Tyrosine modifications and inactivation of active site manganese superoxide dismutase mutant (Y34F) by peroxynitrite.  Arch Biochem Biophys. 1999;  366 82-88
    CrossrefPubMedGoogle Scholar
  • 143 Aulak K S, Miyagi M, Yan L, West K A, Massillon D, Crabb J W, Stuehr D J. Proteomic method identifies proteins nitrated in vivo during inflammatory challenge.  Proc Natl Acad Sci USA. 2001;  98 12 056-12 061
    PubMedGoogle Scholar
  • 144 Bolanos J P, Almeida A, Fernandez E, Medina J M, Land J M, Clark J B, Heales S J. Potental mechanisms for nitric oxide-mediated impairment of brain mitochondrial energy metabolism.  Biochem Soc Trans. 1997;  25 944-949
    PubMedGoogle Scholar
  • 145 Dawson V L, Brahmbhatt H P, Mong J A, Dawson T M. Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures.  Neuropharmacology. 1994;  33 1425-1430
    CrossrefPubMedGoogle Scholar
  • 146 Dawson V L, Dawson T M. Nitric oxide neurotoxicity.  J Chem Neuroanat. 1996;  10 179-190
    CrossrefPubMedGoogle Scholar
  • 147 Nogawa S, Forster C, Zhang F, Magayama M, Ross M E, Iadecola C. Interaction between inducible nitric oxide sinthase and cycloxygenase-2 after cerebral ischemia.  Proc Natl Acad Sci USA. 1998;  95 10 966-10 971
    PubMedGoogle Scholar
  • 148 Klein R, Klein B E, Moss S E, Davis M D, DeMets D L. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years.  Arch Ophthalmol. 1984;  19 520-526
    PubMedGoogle Scholar
  • 149 Warpeha K M, Xu W, Liu L, Charles I G, Patterson C C, Ah-Fat F, Harding S, Hart P M, Chakravarthy U, Hughes A E. Genotyping and functional analysis of a polymorphism (CCTTT)(n) repeat of NOS2A in diabetic retinopathy.  FASEB J. 1999;  19 1825-1832
    PubMedGoogle Scholar
  • 150 Taverna M J, Sola A, Guyot-Argenton C, Pacher N, Bruzzo F, Chevalier A, Slama G, Reach G, Selam J L. eNOS4 polymorphism of the endothelial nitric oxide synthase predicts risk for severe diabetic retinopathy.  Diabet Med. 2002;  19 240-5
    CrossrefPubMedGoogle Scholar
  • 151 Tsukada T, Yokoyama K, Arai T, Takemoto F, Hara S, Yamada A, Kawaguchi Y, Hosoya T, Igari J. Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans.  Biochem Biophys Res Commun. 1998;  19 190-193
    PubMedGoogle Scholar
  • 152 Kumaramanickavel G, Sripriya S, Vellanki R N, Upadyay N K, Badrinath S S, Rajendran V, Sukumar B, Ramprasad V L, Sharma T. Inducible nitric oxide synthase gene and diabetic retinopathy in Asian Indian patients.  Clin Genet. 2002;  61 344-348
    CrossrefPubMedGoogle Scholar
  • 153 Ando A, Yang A, Nambu H, Campochiaro P A. Blockade of nitric-oxide synthase reduces choroidal neovascularization.  Mol Pharmacol. 2002;  62 539-544
    CrossrefPubMedGoogle Scholar
  • 154 Hangai M, Miyamoto K, Hiroi K, Tujikawa A, Ogura Y, Honda Y, Yoshimura N. Roles of constitutive nitric oxide synthase in postischemic rat retina.  Invest Ophthalmol Vis Sci. 1999;  40 450-458
    PubMedGoogle Scholar
  • 155 Parmentier-Batteur S, Bohme G A, Lerouet D, Zhou-Ding L, Beray D, Margaill I. et al . Antisense oligodeoxynucleotide to inducible nitric oxide synthase protects against transient focal cerebral ischemia-induced brain injury.  J Cereb Blood Flow Metab. 2001;  19 15-21
    PubMedGoogle Scholar
  • 156 Hammes H P, Martin S, Federlin K, Geusen K, Brownlee M. Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy.  Proc Natl Acad Sci USA. 1991;  88 11 555-11 558
    PubMedGoogle Scholar
  • 157 Tilton R G, Chang K, Hasan K S, Chang K, Hasan K S, Smith S R, Petrash J M, Misko T P, Moore W M, Currie M G, Corbett J A, McDaniel M L. Prevention of diabetic vascular dysfunction by guanidines.  Inhibition of nitric oxide synthase versus advanced glycation end-product formation Diabetes. 1993;  42 221-232
    PubMedGoogle Scholar
  • 158 Morrish N J, Stevens L K, Fuller J H, Jarrett R J, Keen H. Risk factors for macrovascular disease in diabetes mellitus: the London follow-up to the WHO Multinational Study of Vascular Disease in Diabetics.  Diabetologia. 1991;  34 590-594
    CrossrefPubMedGoogle Scholar
  • 159 Schachinger V, Britten M B, Zeiher A M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease.  Circulation.. 2000;  101 1899 -1906
    CrossrefPubMedGoogle Scholar
  • 160 Rosen P, Du X, Sui G Z. Molecular mechanisms of endothelial dysfunction in the diabetic heart.  Adv Exp Med Biol. 2001;  498 75-86
    PubMedGoogle Scholar
  • 161 Federici M, Menghini R, Mauriello A, Hribal M L, Ferrelli F, Lauro D, Sbraccia P, Spagnoli L G, Sesti G, Lauro R. Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosilation modification of signaling proteins in human coronary endothelial cells.  Circulation. 2002;  106 466-472
    CrossrefPubMedGoogle Scholar
  • 162 Adam J M, Ettelaie C, Naseem K M, James N J, Bradley N J, Bruckdorfer K R. Modification of tissue factor by peroxynitrite influences its procoagulant activity.  FEBS Lett 1998;. 16;  429 347-50
    PubMedGoogle Scholar
  • 163 Napoli C, Lerman L O, de Nigris F, Loscalzo J, Ignarro L J. Glycoxidized low-density lipoprotein downregulates endothelial nitric oxide synthase in human coronary cells.  J Am Coll Cardiol. 2002;  40 1515-22
    CrossrefPubMedGoogle Scholar
  • 164 Huang P L, Huang Z, Mashimo H, Bloch K D, Moskowitz M A, Bevan J A, Fishman M C. Hypertension in mice lacking the gene for endothelial nitric oxide synthase.  Nature. 1995;  377 239 - 242
    CrossrefPubMedGoogle Scholar
  • 165 Moroi M, Zhang L, Yasuda T, Virmani R, Gold H K, Fishman M C, Huang P L. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice.  J Clin Invest. 1998;  101 1225 - 1232
    PubMedGoogle Scholar
  • 166 Sampaio R C, Tanus-Santos J E, Melo S E, Hyslop S, Franchini K G, Luca I A, Moreno H Jr. Hypertension plus diabetes mimics the cardiomyopathy induced by nitric oxide inhibition in rats.  Chest. 2002;  122 1412-1420
    CrossrefPubMedGoogle Scholar
  • 167 Egashira K, Katsuda Y, Mohri M, Kuga T, Tagawa T, Shimokawa H, Takeshita A. Basal release of endothelium-derived nitric oxide at site of spasm in patients with variant angina.  J Am Coll Cardiol. 1996;  27 1444-1449
    CrossrefPubMedGoogle Scholar
  • 168 Quyyumi A A, Dakak N, Andrews N P, Husain S, Arora S, Gilligan D M, Panza J A, Cannon R O 3rd. Nitric oxide activity in the human coronary circulation: Impact of risk factors for coronary atherosclerosis.  J Clin Invest. 1995;  95 1747-1755
    PubMedGoogle Scholar
  • 169 Kobayashi T, Kamata K. Effect of chronic insulin treatment on NO production and endothelium-dependent relaxation in aortae from established STZ-induced diabetic rats.  Atherosclerosis. 2001;  155 313-320
    CrossrefPubMedGoogle Scholar
  • 170 Huszka M, Kaplar M, Rejto L, Tornai I, Palatka K, Laszlo P, Udvardy M. The association of reduced endothelium derived relaxing factor-NO production with endothelial damage and increased in vivo platelet activation in patients with diabetes mellitus.  Thromb Res. 1997;  86 173-80
    CrossrefPubMedGoogle Scholar
  • 171 Treasure C B, Klein J L, Weintraub W S, Talley J D, Stillabower M E, Kosinski A S, Zhang J, Boccuzzi S J, Cedarholm J C, Alexander R W. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.  N Engl J Med. 1995;  332 481-487
    CrossrefPubMedGoogle Scholar
  • 172 Masumoto A, Hirooka Y, Hironaga K, Eshima K, Setoguchi S, Egashira K, Takeshita A. Effect of pravastatin on endothelial function in patients with coronary artery disease (cholesterol-independent effect of pravastatin).  Am J Cardiol. 2001;  88 1291 - 1294
    CrossrefPubMedGoogle Scholar
  • 173 Tsunekawa T, Hayashi T, Kano H, Sumi D, Matsui-Hirai H, Thakur N K, Egashira K, Iguchi A. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days.  Circulation. 2001;  104 376-379
    PubMedGoogle Scholar
  • 174 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes.  Circulation. 2001;  104 365-372
    CrossrefPubMedGoogle Scholar
  • 175 Trovati M, Anfossi G, Massucco P, Mattiello L, Costamagna C, Piretto V, Mularoni E, Cavalot F, Bosia A, Ghigo D. Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3',5'-cyclic monophosphate and adenosine-3'-5'-cyclic monophosphate.  Diabetes. 1997;  46 742-749
    PubMedGoogle Scholar
  • 176 Cooke J P, Dzau V J. Nitric oxide synthase: Role in the genesis of vascular disease.  Annu Rev Med. 1997;  48 489-509
    CrossrefPubMedGoogle Scholar
  • 177 Liao J K. Endothelium and acute coronary syndromes.  Clin Chem. 1998;  44 1799-1808
    PubMedGoogle Scholar
  • 178 Dandona P, Aljada A, Mohanty P. The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm.  Diabetologia. 2002;  45 924-930
    CrossrefPubMedGoogle Scholar
  • 179 Aljada A, Saadeh R, Assian E, Ghanim H, Dandona P. Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide.  J Clin Endocrinol Metab. 2000;  85 2572-2575
    CrossrefPubMedGoogle Scholar
  • 180 Aljada A, Ghanim H, Saadeh R, Dandona P. Insulin inhibits NF-kB and MCP-1 expression in human aortic endothelial cells.  J Clin Endocrinol Metab. 2001;  86 450-453
    CrossrefPubMedGoogle Scholar
  • 181 Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S. Insulin inhibits intranuclear nuclear factor kB and stimulates IkB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?.  J Clin Endocrinol Metab. 2001;  86 3257-3265
    CrossrefPubMedGoogle Scholar
  • 182 Ghanim H, Garg R, Aljada A, Mohanty P, Kumbkarni Y, Assian E, Hamouda W, Dandona P. Suppression of nuclear factor-kB and stimulation of inhibitor kB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese.  J Clin Endocrinol Metab. 2001;  86 1306-1312
    CrossrefPubMedGoogle Scholar
  • 183 Aljada A, Ghanim H, Assian E, Dandona P. Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide sinthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells.  Metabolism. 2002;  51 487-491
    CrossrefPubMedGoogle Scholar
  • 184 Numaguchi K, Egashira K, Takemoto M, Kadokami T, Shimokawa H, Sueishi K, Takeshita A. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats.  Hypertension. 1995;  26 957-962
    PubMedGoogle Scholar
  • 185 Takemoto M, Egashira K, Usui M, Numaguchi K, Tomita H, Tsutsui H, Shimokawa H, Sueishi K, Takeshita A. Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats.  J Clin Invest. 1997;  99 278-287
    CrossrefPubMedGoogle Scholar
  • 186 Takemoto M, Egashira K, Tomita H, Usui M, Okamoto H, Kitabatake A, Shimokawa H, Sueishi K, Takeshita A. Chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade: Effects on cardiovascular remodeling in rats induced by the long-term blockade of nitric oxide synthesis.  Hypertension. 1997;  30 1621-1627
    PubMedGoogle Scholar
  • 187 Tomita H, Egashira K, Kubo-Inoue M, Usui M, Koyanagi M, Shimokawa H, Takeya M, Yoshimura T, Takeshita A. Inhibition of NO synthesis induces inflammatory changes and monocyte chemoattractant protein-1 expression in rat hearts and vessels.  Arterioscler Thromb Vasc Biol. 1998;  18 1456-1464
    PubMedGoogle Scholar
  • 188 Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi M, Katoh M, Yamamoto H, Tamaki K, Shimokawa H, Takeshita A. Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats.  Hypertension. 1998;  32 273-279
    PubMedGoogle Scholar
  • 189 Kubo-Inoue M, Egashira K, Usui M, Takemoto M, Ohtani K, Katoh M, Shimokawa H, Takeshita A. Long-term inhibition of nitric oxide synthesis increases arterial thrombogenecity through angiotensin II-induced expression of tissue factor and resultant production of thrombin in rats.  Am J Physiol Heart Circ Physiol. 2002;  282 H1478-H1484
    CrossrefPubMedGoogle Scholar
  • 190 Galis Z S, Khatri J J. Matrix metalloproteinases in vascular remodelling and atherogenesis: the good, the bad, the ugly.  Circ Res. 2002;  90 251-262
    PubMedGoogle Scholar
  • 191 Usui M, Egashira K, Kitamoto S, Koyanagi M, Katoh M, Kataoka C, Shimokawa H, Takeshita A. Pathogenic role of oxidative stress in vascular angiotensin-converting enzyme activation in long-term blockade of nitric oxide synthesis in rats.  Hypertension. 1999;  34 546-551
    PubMedGoogle Scholar
  • 192 Kitamoto S, Egashira K, Kataoka C, Usui M, Koyanagi M, Takemoto M, Takeshita A. Chronic inhibition of nitric oxide synthesis in rats increases aortic superoxide anion production via the action of angiotensin II.  J Hypertens. 2000;  18 1795 - 1800
    CrossrefPubMedGoogle Scholar
  • 193 Koyanagi M, Egashira K, Kitamoto S, Ni W, Shimokawa H, Takeya M, Yoshimura T. Role of monocyte chemoattractant protein-1 in cardiovascular remodelling induced by chronic blockade of nitric oxide synthesis.  Circulation. 2000;  102 2243-2248
    PubMedGoogle Scholar
  • 194 Koyanagi M, Egashira K, Kubo-Inoue M, Usui M, Kitamoto S, Tomita H, Shimokawa H, Takeshita A. Role of transforming growth factor-beta 1 in cardiovascular inflammatory changes induced by chronic inhibition of nitric oxide synthesis.  Hypertension. 2000;  35 86-90
    PubMedGoogle Scholar

F. Chiarelli, M. D.

Department of Pediatrics

University of Chieti · Ospedale Policlinico · Via dei Vestini 5 · 66100 Chieti · Italy

Telefon: +39(871)358015

Fax: +39(871)574831

eMail: chiarelli@unich.it

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