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ACE Inhibitors and Angiotensin II Receptor Antagonists

  • A. Dendorfer
  • P. Dominiak
  • H. Schunkert
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 170)

Abstract

The biological actions of angiotensin II (ANG), the most prominent hormone of the renin-angiotensin-aldosterone system (RAAS), may promote the development of atherosclerosis in many ways. ANG aggravates hypertension, metabolic syndrome, and endothelial dysfunction, and thereby constitutes a major risk factor for cardiovascular disease. The formation of atherosclerotic lesions involves local uptake, synthesis and oxidation of lipids, inflammation, as well as cellular migration and proliferation—mechanisms that may all be enhanced by ANG via its AT1 receptor. ANG may also increase the risk of acute thrombosis by destabilizing atherosclerotic plaques and enhancing the activity of thrombocytes and coagulation. After myocardial infarction, ANG promotes myocardial remodeling and fibrosis, and its many pathological mechanisms deteriorate the prognosis of these high-risk patients in particular. Therapeutically, inhibitors of the angiotensin I-converting enzyme (ACEI) and AT1 receptor blockers (ARB) are available to suppress the generation and cellular signaling of ANG, respectively. Despite major differences in the efficacy of ANG suppression and the modulation of other hormones and receptors, both classes of drugs are generally effective in attenuating numerous pathomechanisms of ANG in vitro, and in diminishing the development of atherosclerotic lesions and restenosis after angioplasty in various animal models. In clinical therapy, ACEI and ACE are well-tolerated antihypertensive drugs that also improve the prognosis of heart failure patients. After myocardial infarction and in stable coronary heart disease, ACEI have been shown to reduce mortality in a manner independent of hemodynamic alterations. However, there is little evidence that inhibitors of the RAAS may be effective against arterial restenosis, and a possible benefit of these substances compared to other antihypertensive drugs in the primary prevention of coronary heart disease in hypertensive patients is still a matter of debate, possibly depending on the specific substance and condition being investigated. As such, the general clinical efficacy of ACEI and ARB may be due to a positive influence on hemodynamic load, vascular function, myocardial remodeling, and neuro-humoral regulation, rather than to a direct attenuation of the atherosclerotic process. Further therapeutic advances may be achieved by identifying optimum drugs, patient populations, and treatment protocols.

Keywords

Renin-angiotensin-aldosterone system Angiotensin I Angiotensin I-converting enzyme ACE inhibitor Angiotensin AT1-receptor 

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References

  1. Abe J, Deguchi J, Matsumoto T, Takuwa N, Noda M, Ohno M, Makuuchi M, Kurokawa K, Takuwa Y (1997) Stimulated activation of platelet-derived growth factor receptor in vivo in balloon-injured arteries: a link between angiotensin II and intimal thickening. Circulation 96:1906–1913PubMedGoogle Scholar
  2. Akasu M, Urata H, Kinoshita A, Sasaguri M, Ideishi M, Arakawa K (1998) Differences in tissue angiotensin II-forming pathways by species and organs in vitro. Hypertension 32:514–520PubMedGoogle Scholar
  3. Anderson TJ, Elstein E, Haber H, Charbonneau F (2000) Comparative study of ACEinhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilationinpatientswith coronary disease (BANFFstudy). J Am Coll Cardiol 35:60–66CrossRefPubMedGoogle Scholar
  4. Bonner G, Preis S, Schunk U, Toussaint C, Kaufmann W (1990) Hemodynamic effects of bradykinin on systemic and pulmonary circulation in healthy and hypertensive humans. J Cardiovasc Pharmacol 15Suppl 6:S46–S56Google Scholar
  5. Brand K, Page S, Rogler G, Bartsch A, Brandl R, Knuechel R, Page M, Kaltschmidt C, Baeuerle PA, Neumeier D (1996) Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest 97:1715–1722PubMedGoogle Scholar
  6. Brasch H, Sieroslawski L, Dominiak P (1993) Angiotensin II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors. Hypertension 22:699–704PubMedGoogle Scholar
  7. Brede M, Hadamek K, Meinel L, Wiesmann F, Peters J, Engelhardt S, Simm A, Haase A, Lohse MJ, Hein L (2001) Vascular hypertrophy and increased P70S6 kinase in mice lacking the angiotensin II AT(2) receptor. Circulation 104:2602–2607PubMedGoogle Scholar
  8. Brewster UC, Setaro JF, Perazella MA (2003) The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci 326:15–24CrossRefPubMedGoogle Scholar
  9. Cambien F, Costerousse O, Tiret L, Poirier O, Lecerf L, Gonzales MF, Evans A, Arveiler D, Cambou JP, Luc G,. (1994) Plasma level and gene polymorphism of angiotensin-converting enzyme in relation to myocardial infarction. Circulation 90:669–676PubMedGoogle Scholar
  10. Cambien F, Evans A (1995) Angiotensin I converting enzyme gene polymorphism and coronary heart disease. Eur Heart J 16Suppl K:13–22Google Scholar
  11. Candido R, Jandeleit-Dahm KA, Cao Z, Nesteroff SP, Burns WC, Twigg SM, Dilley RJ, Cooper ME, Allen TJ (2002) Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice. Circulation 106:246–253CrossRefPubMedGoogle Scholar
  12. Carey RM, Howell NL, Jin XH, Siragy HM (2001) Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats. Hypertension 38:1272–1277PubMedGoogle Scholar
  13. Cashin-Hemphill L, Holmvang G, Chan RC, Pitt B, Dinsmore RE, Lees RS (1999) Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: no answer yet. QUIET Investigators. QUinapril Ischemic Event Trial. Am J Cardiol 83:43–47CrossRefPubMedGoogle Scholar
  14. Chen H, Li D, Sawamura T, Inoue K, Mehta JL (2000) Upregulation of LOX-1 expression in aorta of hypercholesterolemic rabbits: modulation by losartan. Biochem Biophys Res Commun 276:1100–1104PubMedGoogle Scholar
  15. Chen M, Masaki T, Sawamura T (2002) LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther 95:89–100CrossRefPubMedGoogle Scholar
  16. Cohn JN, Tognoni G (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 345:1667–1675CrossRefPubMedGoogle Scholar
  17. Collins T, Cybulsky MI (2001) NF-kappaB: pivotalmediator or innocent bystander in atherogenesis? J Clin Invest 107:255–264PubMedGoogle Scholar
  18. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, Rigoni A, Pastorino AM, Lo C, V, Sawamura T (2000) Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species. J Biol Chem 275:12633–12638CrossRefPubMedGoogle Scholar
  19. Cui T, Nakagami H, Iwai M, Takeda Y, Shiuchi T, Daviet L, Nahmias C, Horiuchi M (2001) Pivotal role of tyrosine phosphatase SHP-1 in AT2 receptor-mediated apoptosis in rat fetal vascular smooth muscle cell. Cardiovasc Res 49:863–871CrossRefPubMedGoogle Scholar
  20. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H (2002) Cardiovascularmorbidity andmortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:995–1003CrossRefPubMedGoogle Scholar
  21. Danser AH (2003) Local renin-angiotensin systems: the unanswered questions. Int J Biochem Cell Biol 35:759–768CrossRefPubMedGoogle Scholar
  22. Danser AH, Derkx FH, Hense HW, Jeunemaitre X, Riegger GA, Schunkert H (1998) Angiotensinogen (M235T) and angiotensin-converting enzyme (I/D) polymorphisms in association with plasma renin and prorenin levels. J Hypertens 16:1879–1883PubMedGoogle Scholar
  23. Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, Schunkert H (1995) Angiotensin-converting enzyme in the human heart. Effect of the deletion/ insertion polymorphism. Circulation 92:1387–1388PubMedGoogle Scholar
  24. Daugherty A, Manning MW, Cassis LA (2001) Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. Br J Pharmacol 134:865–870CrossRefPubMedGoogle Scholar
  25. Delafontaine P, Lou H (1993) Angiotensin II regulates insulin-like growth factor I gene expression in vascular smooth muscle cells. J Biol Chem 268:16866–16870PubMedGoogle Scholar
  26. Dendorfer A, Thornagel A, Raasch W, Grisk O, Tempel K, Dominiak P (2002) Angiotensin II induces catecholamine release by direct ganglionic excitation. Hypertension 40:348–354PubMedGoogle Scholar
  27. DiBona GF (2002) Sympathetic nervous system and the kidney in hypertension. Curr Opin Nephrol Hypertens 11:197–200CrossRefPubMedGoogle Scholar
  28. Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ (1996) Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation 94:2756–2767PubMedGoogle Scholar
  29. Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM (1997) Angiotensin II induces apoptosis of humanendothelial cells. Protective effect of nitric oxide. Circ Res 81:970–976PubMedGoogle Scholar
  30. Ding YA, MacIntyre DE, Kenyon CJ, Semple PF (1985) Potentiation of adrenaline-induced platelet aggregation by angiotensin II. Thromb Haemost 54:717–720PubMedGoogle Scholar
  31. Dostal DE, Baker KM (1999) The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ Res 85:643–650PubMedGoogle Scholar
  32. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMedGoogle Scholar
  33. Dusting GJ, Fennessy P, Yin ZL, Gurevich V (1998) Nitric oxide in atherosclerosis: vascular protector or villain? Clin Exp Pharmacol Physiol Suppl 25:S34–S41Google Scholar
  34. Dzau VJ, Bernstein K, Celermajer D, Cohen J, Dahlof B, Deanfield J, Diez J, Drexler H, Ferrari R, Van Gilst W, Hansson L, Hornig B, Husain A, Johnston C, Lazar H, Lonn E, Luscher T, Mancini J, Mimran A, Pepine C, Rabelink T, Remme W, Ruilope L, Ruzicka M, Schunkert H, Swedberg K, Unger T, Vaughan D, Weber M (2002) Pathophysiologic and therapeutic importance of tissue ACE: a consensus report. Cardiovasc Drugs Ther 16:149–160PubMedGoogle Scholar
  35. Eguchi S, Numaguchi K, Iwasaki H, Matsumoto T, Yamakawa T, Utsunomiya H, Motley ED, Kawakatsu H, Owada KM, Hirata Y, Marumo F, Inagami T (1998) Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J Biol Chem 273:8890–8896PubMedGoogle Scholar
  36. Elmfeldt D, Olofsson B, Meredith P (2002) The relationships between dose and antihypertensive effect of four AT1-receptor blockers. Differences in potency and efficacy. Blood Press 11:293–301CrossRefPubMedGoogle Scholar
  37. Endo-Mochizuki Y, Mochizuki N, Sawa H, Takada A, Okamoto H, Kawaguchi H, Nagashima K, Kitabatake A (1995) Expression of renin and angiotensin-converting enzyme in human hearts. Heart Vessels 10:285–293PubMedGoogle Scholar
  38. Esther CR, Marino EM, Howard TE, Machaud A, Corvol P, Capecchi MR, Bernstein KE (1997) The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest 99:2375–2385PubMedGoogle Scholar
  39. Farhy RD, Carretero OA, Ho KL, Scicli AG (1993) Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res 72:1202–1210PubMedGoogle Scholar
  40. Faxon DP (1995) Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the MARCATOR Study, a multicenter, double-blind, placebo-controlled trial of cilazapril. The Multicenter American Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. J Am Coll Cardiol 25:362–369PubMedGoogle Scholar
  41. Fennessy PA, Campbell JH, Mendelsohn FA, Campbell GR (1996) Angiotensin-converting enzyme inhibitors and atherosclerosis: relevance of animal models to human disease. Clin Exp Pharmacol Physiol 23:S30–S32PubMedGoogle Scholar
  42. Fernandez-Alfonso MS, Martorana PA, Licka I, van Even P, Trobisch D, Scholkens BA, Paul M (1997) Early induction of angiotensin I-converting enzyme in rat carotid artery after balloon injury. Hypertension 30:272–277PubMedGoogle Scholar
  43. Feuerstein GZ, Young PR (2000) Apoptosis in cardiac diseases: stress-and mitogen-activated signaling pathways. Cardiovasc Res 45:560–569CrossRefPubMedGoogle Scholar
  44. Fingerle J, Muller RM, Kuhn H, Pech M, Baumgartner HR (1995) Mechanism of inhibition of neointimal formation by the angiotensin-converting enzyme inhibitor cilazapril. A study in balloon catheter-injured rat carotid arteries. Arterioscler Thromb Vasc Biol 15:1945–1950PubMedGoogle Scholar
  45. Fox KM (2003) Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 362:782–788CrossRefPubMedGoogle Scholar
  46. Gibbons GH, Pratt RE, Dzau VJ (1992) Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest 90:456–461PubMedGoogle Scholar
  47. Goldenberg I, Grossman E, Jacobson KA, Shneyvays V, Shainberg A (2001) Angiotensin II-induced apoptosis in rat cardiomyocyte culture: a possible role of AT1 and AT2 receptors. J Hypertens 19:1681–1689PubMedGoogle Scholar
  48. Griendling KK, Ushio-Fukai M, Lassegue B, Alexander RW (1997) Angiotensin II signaling in vascular smooth muscle. New concepts. Hypertension 29:366–373PubMedGoogle Scholar
  49. Griffin SA, Brown WC, MacPherson F, McGrath JC, Wilson VG, Korsgaard N, Mulvany MJ, Lever AF (1991) Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism. Hypertension 17:626–635PubMedGoogle Scholar
  50. Hamdan AD, Quist WC, Gagne JB, Feener EP (1996) Angiotensin-converting enzyme inhibition suppresses plasminogen activator inhibitor-1 expression in the neointima of balloon-injured rat aorta. Circulation 93:1073–1078PubMedGoogle Scholar
  51. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE (1999) Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 353:611–616PubMedGoogle Scholar
  52. Harris EL, Phelan EL, Thompson CM, Millar JA, Grigor MR (1995) Heart mass and blood pressure have separate genetic determinants in the New Zealand genetically hypertensive (GH) rat. J Hypertens 13:397–404PubMedGoogle Scholar
  53. Hattori Y, Matsumura M, Kasai K (2003) Vascular smoothmuscle cell activation by C-reactive protein. Cardiovasc Res 58:186–195CrossRefPubMedGoogle Scholar
  54. Hayek T, Kaplan M, Raz A, Keidar S, Coleman R, Aviram M (2002) Ramipril administration to atherosclerotic mice reduces oxidized low-density lipoprotein uptake by their macrophages and blocks the progression of atherosclerosis. Atherosclerosis 161:65–74PubMedGoogle Scholar
  55. Hayek T, Pavlotzky E, Hamoud S, Coleman R, Keidar S, Aviram M, Kaplan M (2003) Tissue angiotensin-converting-enzyme (ACE) deficiency leads to a reduction in oxidative stress and in atherosclerosis. Studies in ACE-knockout mice type 2. Arterioscler Thromb Vasc Biol 23:2090–2096CrossRefPubMedGoogle Scholar
  56. Herizi A, Jover B, Bouriquet N, Mimran A (1998) Prevention of the cardiovascular and renal effects of angiotensin II by endothelin blockade. Hypertension 31:10–14PubMedGoogle Scholar
  57. Hernandez-Presa M, Bustos C, Ortego M, Tunon J, Renedo G, Ruiz-Ortega M, Egido J (1997) Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation 95:1532–1541PubMedGoogle Scholar
  58. Hernandez-Presa MA, Bustos C, Ortego M, Tunon J, Ortega L, Egido J (1998) ACE inhibitor quinapril reduces the arterial expression of NF-kappa B-dependent proinflammatory factors but not of collagen I in a rabbit model of atherosclerosis. Am J Pathol 153:1825–1837PubMedGoogle Scholar
  59. Hilgers KF, Veelken R, Muller DN, Kohler H, Hartner A, Botkin SR, Stumpf C, Schmieder RE, Gomez RA (2001) Renin uptake by the endothelium mediates vascular angiotensin formation. Hypertension 38:243–248PubMedGoogle Scholar
  60. Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, Gans RO, Janssen WM, Grobbee DE, de Jong PE (2002)Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 106:1777–1782CrossRefPubMedGoogle Scholar
  61. Hope S, Brecher P, Chobanian AV (1999) Comparison of the effects of AT1 receptor blockade and angiotensin converting enzyme inhibition on atherosclerosis. Am J Hypertens 12:28–34CrossRefPubMedGoogle Scholar
  62. Hornig B, Arakawa N, Haussmann D, Drexler H (1998) Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure. Circulation 98:2842–2848PubMedGoogle Scholar
  63. Hornig B, Kohler C, Schlink D, Tatge H, Drexler H (2003) AT1-receptor antagonism improves endothelial function in coronary artery disease by a bradykinin/B2-receptor-dependent mechanism. Hypertension 41:1092–1095PubMedGoogle Scholar
  64. Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A, Tatge H, Drexler H (2001) Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 103:799–805PubMedGoogle Scholar
  65. Ichihara S, Senbonmatsu T, Price E Jr, Ichiki T, Gaffney FA, Inagami T (2001) Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation 104:346–351PubMedGoogle Scholar
  66. Igarashi M, Hirata A, Yamaguchi H, Tsuchiya H, Ohnuma H, Tominaga M, Daimon M, Kato T (2001) Candesartan inhibits carotid intimal thickening and ameliorates insulin resistance in balloon-injured diabetic rats. Hypertension 38:1255–1259PubMedGoogle Scholar
  67. Ihara M, Urata H, Kinoshita A, Suzumiya J, Sasaguri M, Kikuchi M, Ideishi M, Arakawa K (1999) Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension 33:1399–1405PubMedGoogle Scholar
  68. Jacob HJ, Lindpaintner K, Lincoln SE, Kusumi K, Bunker RK, Mao YP, Ganten D, Dzau VJ, Lander ES (1991) Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67:213–224CrossRefPubMedGoogle Scholar
  69. Kato H, Suzuki H, Tajima S, Ogata Y, Tominaga T, Sato A, Saruta T (1991) Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens 9:17–22PubMedGoogle Scholar
  70. Keidar S (1998) Angiotensin, LDL peroxidation and atherosclerosis. Life Sci 63:1–11PubMedGoogle Scholar
  71. Keidar S, Attias J, Coleman R, Wirth K, Scholkens B, Hayek T (2000) Attenuation of atherosclerosis in apolipoprotein E-deficient mice by ramipril is dissociated from its antihypertensive effect and from potentiation of bradykinin. J Cardiovasc Pharmacol 35:64–72PubMedGoogle Scholar
  72. Keidar S, Attias J, Heinrich R, Coleman R, Aviram M (1999) Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis. Atherosclerosis 146:249–257PubMedGoogle Scholar
  73. Keidar S, Kaplan M, Hoffman A, Aviram M (1995) Angiotensin II stimulates macrophage-mediated oxidation of low density lipoproteins. Atherosclerosis 115:201–215PubMedGoogle Scholar
  74. Kim S, Iwao H (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 52:11–34PubMedGoogle Scholar
  75. Kim S, Izumi Y, Yano M, Hamaguchi A, Miura K, Yamanaka S, Miyazaki H, Iwao H (1998) Angiotensin blockade inhibits activation of mitogen-activated protein kinases in rat balloon-injured artery. Circulation 97:1731–1737PubMedGoogle Scholar
  76. Kim S, Kawamura M, Wanibuchi H, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Iwao H (1995) Angiotensin II type 1 receptor blockade inhibits the expression of immediate-early genes and fibronectin in rat injured artery. Circulation 92:88–95PubMedGoogle Scholar
  77. Koch W, Mehilli J, von Beckerath N, Bottiger C, Schomig A, Kastrati A (2003) Angiotensin I-converting enzyme (ACE) inhibitors and restenosis after coronary artery stenting in patients with the DD genotype of the ACE gene. J Am Coll Cardiol 41:1957–1961CrossRefPubMedGoogle Scholar
  78. Kranzhofer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kubler W (1999) Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 19:1623–1629PubMedGoogle Scholar
  79. Kume N, Moriwaki H, Kataoka H, Minami M, Murase T, Sawamura T, Masaki T, Kita T (2000) Inducible expression of LOX-1, a novel receptor for oxidized LDL, in macrophages and vascular smooth muscle cells. Ann N Y Acad Sci 902:323–327PubMedGoogle Scholar
  80. Kurisu S, Ozono R, Oshima T, Kambe M, Ishida T, Sugino H, Matsuura H, Chayama K, Teranishi Y, Iba O, Amano K, Matsubara H (2003) Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension 41:99–107PubMedGoogle Scholar
  81. Lassegue B, Clempus RE (2003) Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 285:R277–R297PubMedGoogle Scholar
  82. Li D, Mehta JL (2000) Antisense to LOX-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells. Circulation 101:2889–2895PubMedGoogle Scholar
  83. Li D, Singh RM, Liu L, Chen H, Singh BM, Kazzaz N, Mehta JL (2003) Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells. Cardiovasc Res 57:238–243PubMedGoogle Scholar
  84. Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL (1999) Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res 84:1043–1049PubMedGoogle Scholar
  85. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S (2002) Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:1004–1010PubMedGoogle Scholar
  86. Lindpaintner K, Lee M, Larson MG, Rao VS, Pfeffer MA, Ordovas JM, Schaefer EJ, Wilson AF, Wilson PW, Vasan RS, Myers RH, Levy D (1996) Absence of association or genetic linkage between the angiotensin-converting-enzyme gene and left ventricular mass. N Engl J Med 334:1023–1028PubMedGoogle Scholar
  87. Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F, Buring J, Hennekens CH (1995) A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 332:706–711PubMedGoogle Scholar
  88. Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA (1995) Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 47:25–49PubMedGoogle Scholar
  89. Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA (1997) Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest 99:1926–1935PubMedGoogle Scholar
  90. Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley W, Teo K (2001) Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 103:919–925PubMedGoogle Scholar
  91. MacMahon S, Sharpe N, Gamble G, Clague A, Mhurchu CN, Clark T, Hart H, Scott J, White H (2000) Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol 36:438–443CrossRefPubMedGoogle Scholar
  92. Mallat Z, Tedgui A (2000) Apoptosis in the vasculature: mechanisms and functional importance. Br J Pharmacol 130:947–962PubMedGoogle Scholar
  93. Mancini GB (1998) Role of angiotensin-converting enzyme inhibition in reversal of endothelial dysfunction in coronary artery disease. Am J Med 105:40S–47SPubMedGoogle Scholar
  94. Mancini GB (2002) Emerging role of angiotensin II type 1 receptor blockers for the treatment of endothelial dysfunction and vascular inflammation. Can J Cardiol 18:1309–1316PubMedGoogle Scholar
  95. Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B (1996) Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation 94:258–265PubMedGoogle Scholar
  96. Matsubara H (1998) Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res 83:1182–1191PubMedGoogle Scholar
  97. Matsumoto K, Morishita R, Moriguchi A, Tomita N, Aoki M, Sakonjo H, Matsumoto K, Nakamura T, Higaki J, Ogihara T (2001) Inhibition of neointima by angiotensin-converting enzyme inhibitor in porcine coronary artery balloon-injury model. Hypertension 37:270–274PubMedGoogle Scholar
  98. Mazzolai L, Nussberger J, Aubert JF, Brunner DB, Gabbiani G, Brunner HR, Pedrazzini T (1998) Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension 31:1324–1330PubMedGoogle Scholar
  99. Mehta JL, Li D (2002) Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor. J Am Coll Cardiol 39:1429–1435CrossRefPubMedGoogle Scholar
  100. Meurice T, Bauters C, Hermant X, Codron V, VanBelle E, Mc Fadden EP, Lablanche J, Bertrand ME, Amouyel P (2001) Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomised, double-blind, placebo-controlled trial. Lancet 357:1321–1324CrossRefPubMedGoogle Scholar
  101. Mitani H, Bandoh T, Kimura M, Totsuka T, Hayashi S (1996) Increased activity of vascular ACE related to atherosclerotic lesions in hyperlipidemic rabbits. Am J Physiol 271:H1065–H1071PubMedGoogle Scholar
  102. Miyazaki M, Sakonjo H, Takai S (1999) Anti-atherosclerotic effects of an angiotensin converting enzyme inhibitor and an angiotensin II antagonist in Cynomolgus monkeys fed a high-cholesterol diet. Br J Pharmacol 128:523–529CrossRefPubMedGoogle Scholar
  103. Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz M, August M, Kleschyov AL, Tsilimingas N, Walter U, Forstermann U, Meinertz T, Griendling K, Munzel T (2002) Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90:E58–E65CrossRefPubMedGoogle Scholar
  104. Montgomery HE, Clarkson P, Dollery CM, Prasad K, Losi MA, Hemingway H, Statters D, Jubb M, Girvain M, Varnava A, World M, Deanfield J, Talmud P, McEwan JR, McKenna WJ, Humphries S (1997) Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation 96:741–747PubMedGoogle Scholar
  105. Morawietz H, Duerrschmidt N, Niemann B, Galle J, Sawamura T, Holtz J (2001) Induction of the oxLDL receptor LOX-1 by endothelin-1 in human endothelial cells. Biochem Biophys Res Commun 284:961–965CrossRefPubMedGoogle Scholar
  106. Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K, Zerkowski HR, Sawamura T, Holtz J (1999) Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation 100:899–902PubMedGoogle Scholar
  107. Morishige K, Shimokawa H, Matsumoto Y, Eto Y, Uwatoku T, Abe K, Sueishi K, Takeshita A (2003) Overexpression of matrix metalloproteinase-9 promotes intravascular thrombus formation in porcine coronary arteries in vivo. Cardiovasc Res 57:572–585CrossRefPubMedGoogle Scholar
  108. Moriwaki H, Kume N, Kataoka H, Murase T, Nishi E, Sawamura T, Masaki T, Kita T (1998) Expression of lectin-like oxidized low density lipoprotein receptor-1 in human and murine macrophages: upregulated expression by TNF-alpha. FEBS Lett 440:29–32CrossRefPubMedGoogle Scholar
  109. Naftilan AJ, Pratt RE, Dzau VJ (1989) Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest 83:1419–1424PubMedGoogle Scholar
  110. Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L, Horiuchi M, Pratt RE, Dzau VJ (1995) The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci U S A 92:10663–10667PubMedGoogle Scholar
  111. Nakamura S, Nakamura I, Ma L, Vaughan DE, Fogo AB (2000) Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo. Kidney Int 58:251–259CrossRefPubMedGoogle Scholar
  112. Napoli C, Cicala C, D'Armiento FP, Roviezzo F, Somma P, de Nigris F, Zuliani P, Bucci M, Aleotti L, Casini A, Franconi F, Cirino G (1999) Beneficial effects of ACE-inhibition with zofenopril on plaque formation and low-density lipoprotein oxidation in watanabe heritable hyperlipidemic rabbits. Gen Pharmacol 33:467–477CrossRefPubMedGoogle Scholar
  113. Napoli C, Ignarro LJ (2001) Nitric oxide and atherosclerosis. Nitric Oxide 5:88–97CrossRefPubMedGoogle Scholar
  114. Nickenig G, Baumer AT, Temur Y, Kebben D, Jockenhovel F, Bohm M(1999) Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation 100:2131–2134PubMedGoogle Scholar
  115. Nickenig G, Roling J, Strehlow K, Schnabel P, Bohm M (1998) Insulin induces upregulation of vascular AT1 receptor gene expression by posttranscriptional mechanisms. Circulation 98:2453–2460PubMedGoogle Scholar
  116. Nickenig G, Sachinidis A, Michaelsen F, Bohm M, Seewald S, Vetter H (1997) Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells. Circulation 95:473–478PubMedGoogle Scholar
  117. Nielsen LB, Stender S, Kjeldsen K, Nordestgaard BG (1994) Effect of angiotensin II and enalapril on transfer of low-density lipoprotein into aortic intima in rabbits. Circ Res 75:63–69PubMedGoogle Scholar
  118. Ohishi M, Ueda M, Rakugi H, Naruko T, Kojima A, Okamura A, Higaki J, Ogihara T (1999) Relative localization of angiotensin-converting enzyme, chymase and angiotensin II in human coronary atherosclerotic lesions. J Hypertens 17:547–553CrossRefPubMedGoogle Scholar
  119. Ohmichi N, Iwai N, Maeda K, Shimoike H, Nakamura Y, Izumi M, Sugimoto Y, Kinoshita M (1996) Genetic basis of left ventricular remodeling after myocardial infarction. Int J Cardiol 53:265–272CrossRefPubMedGoogle Scholar
  120. Palatini P (2001) Sympathetic overactivity in hypertension: a risk factor for cardiovascular disease. Curr Hypertens Rep 3(Suppl 1):S3–S9PubMedGoogle Scholar
  121. Peters S, Gotting B, Trummel M, Rust H, Brattstrom A (2001) Valsartan for prevention of restenosis after stenting of type B2/C lesions: the VAL-PREST trial. J Invasive Cardiol 13:93–97PubMedGoogle Scholar
  122. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S (2003) Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 362:759–766CrossRefPubMedGoogle Scholar
  123. Pinto YM, Tian X, Costerousse O, Stula M, Franz WM, Paul M (1997) Cardiac overexpression of angiotensin-converting enzyme in transgenic rats augments cardiac hypertrophy. Circulation 96:I-629;abstract 3521Google Scholar
  124. Pinto YM, van Gilst WH, Kingma JH, Schunkert H (1995) Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction. Captopril and Thrombolysis Study Investigators. J Am Coll Cardiol 25:1622–1626CrossRefPubMedGoogle Scholar
  125. Pitt B, O'Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, Bass T, Pepine C, Texter M, Haber H, Uprichard A, Cashin-Hemphill L, Lees RS (2001) The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol 87:1058–1063CrossRefPubMedGoogle Scholar
  126. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B (2000) Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial-the Losartan Heart Failure Survival Study ELITE II. Lancet 355:1582–1587CrossRefPubMedGoogle Scholar
  127. Prasad A, Narayanan S, Husain S, Padder F, Waclawiw M, Epstein N, Quyyumi AA (2000a) Insertion-deletion polymorphism of the ACE gene modulates reversibility of endothelial dysfunction with ACE inhibition. Circulation 102:35–41PubMedGoogle Scholar
  128. Prasad A, Tupas-Habib T, Schenke WH, Mincemoyer R, Panza JA, Waclawin MA, Ellahham S, Quyyumi AA (2000b) Acute and chronic angiotensin-1 receptor antagonism reverses endothelial dysfunction in atherosclerosis. Circulation 101:2349–2354PubMedGoogle Scholar
  129. Rahman ST, Lauten WB, Khan QA, Navalkar S, Parthasarathy S, Khan BV (2002) Effects of eprosartan versus hydrochlorothiazide on markers of vascular oxidation and inflammation and blood pressure (renin-angiotensin system antagonists, oxidation, and inflammation). Am J Cardiol 89:686–690CrossRefPubMedGoogle Scholar
  130. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 97:1916–1923PubMedGoogle Scholar
  131. Rakugi H, Kim DK, Krieger JE, Wang DS, Dzau VJ, Pratt RE (1994a) Induction of angiotensin converting enzyme in the neointima after vascular injury. Possible role in restenosis. J Clin Invest 93:339–346PubMedGoogle Scholar
  132. Rakugi H, Wang DS, Dzau VJ, Pratt RE (1994b) Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation. Circulation 90:449–455PubMedGoogle Scholar
  133. Regitz-Zagrosek V, Friedel N, Heymann A, Bauer P, Neuss M, Rolfs A, Steffen C, Hildebrandt A, Hetzer R, Fleck E (1995) Regulation, chamber localization, and subtype distribution of angiotensin II receptors in human hearts. Circulation 91:1461–1471PubMedGoogle Scholar
  134. Ridker PM (2001) Role of inflammatory biomarkers in prediction of coronary heart disease. Lancet 358:946–948CrossRefPubMedGoogle Scholar
  135. Ross R (1999) Atherosclerosis-an inflammatory disease. N Engl J Med 340:115–126CrossRefPubMedGoogle Scholar
  136. Rueckschloss U, Quinn MT, Holtz J, Morawietz H (2002) Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 22:1845–1851CrossRefPubMedGoogle Scholar
  137. Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Suzuki Y, Mezzano S, Plaza JJ, Egido J (2001) Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension 38:1382–1387PubMedGoogle Scholar
  138. Ruiz-Ortega M, Lorenzo O, Ruperez M, Konig S, Wittig B, Egido J (2000) Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells: molecular mechanisms. Circ Res 86:1266–1272PubMedGoogle Scholar
  139. Rutherford JD, Pfeffer MA, Moye LA, Davis BR, Flaker GC, Kowey PR, Lamas GA, Miller HS, Packer M, Rouleau JL (1994) Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators. Circulation 90:1731–1738PubMedGoogle Scholar
  140. Saward L, Zahradka P (1997) Angiotensin II activates phosphatidylinositol 3-kinase in vascular smooth muscle cells. Circ Res 81:249–257PubMedGoogle Scholar
  141. Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H (2000) Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 101:1372–1378PubMedGoogle Scholar
  142. Schiffrin EL (2001) Role of endothelin-1 in hypertension and vascular disease. Am J Hypertens 14:83S–89SCrossRefPubMedGoogle Scholar
  143. Schuh JR, Blehm DJ, Frierdich GE, McMahon EG, Blaine EH (1993) Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits. J Clin Invest 91:1453–1458PubMedGoogle Scholar
  144. Schunkert H (1997) Polymorphism of the angiotensin-converting enzyme gene and cardiovascular disease. J Mol Med 75:867–875CrossRefPubMedGoogle Scholar
  145. Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH(1990) Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation. J Clin Invest 86:1913–1920PubMedGoogle Scholar
  146. Schunkert H, Sadoshima J, Cornelius T, Kagaya Y, Weinberg EO, Izumo S, Riegger G, Lorell BH (1995) Angiotensin II-induced growth responses in isolated adult rat hearts. Evidence for load-independent induction of cardiac protein synthesis by angiotensin II. Circ Res 76:489–497PubMedGoogle Scholar
  147. Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK (2002) Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res 91:406–413CrossRefPubMedGoogle Scholar
  148. Sharifi BG, LaFleur DW, Pirola CJ, Forrester JS, Fagin JA (1992) Angiotensin II regulates tenascin gene expression in vascular smooth muscle cells. J Biol Chem 267:23910–23915PubMedGoogle Scholar
  149. Siragy HM, Inagami T, Ichiki T, Carey RM (1999) Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci USA 96:6506–6510CrossRefPubMedGoogle Scholar
  150. Soejima H, Ogawa H, Yasue H, Kaikita K, Takazoe K, Nishiyama K, Misumi K, Miyamoto S, Yoshimura M, Kugiyama K, Nakamura S, Tsuji I (1999) Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction. J Am Coll Cardiol 34:983–988CrossRefPubMedGoogle Scholar
  151. Sohn HY, Raff U, Hoffmann A, Gloe T, Heermeier K, Galle J, Pohl U (2000) Differential role of angiotensin II receptor subtypes on endothelial superoxide formation. Br J Pharmacol 131:667–672CrossRefPubMedGoogle Scholar
  152. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL (1989) Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320:915–924PubMedGoogle Scholar
  153. Strawn WB, Chappell MC, Dean RH, Kivlighn S, Ferrario CM (2000) Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia. Circulation 101:1586–1593PubMedGoogle Scholar
  154. Su EJ, Lombardi DM, Siegal J, Schwartz SM (1998) Angiotensin II induces vascular smooth muscle cell replication independent of blood pressure. Hypertension 31:1331–1337PubMedGoogle Scholar
  155. Sun YP, Zhu BQ, Browne AE, Pulukurthy S, Chou TM, Sudhir K, Glantz SA, Deedwania PC, Chatterjee K, Parmley WW (2001) Comparative effects of ACE inhibitors and an angiotensin receptor blocker on atherosclerosis and vascular function. J Cardiovasc Pharmacol Ther 6:175–181PubMedGoogle Scholar
  156. Suzuki J, Iwai M, Nakagami H, Wu L, Chen R, Sugaya T, Hamada M, Hiwada K, Horiuchi M (2002)Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation. Circulation 106:847–853CrossRefPubMedGoogle Scholar
  157. Takai S, Shiota N, Kobayashi S, Matsumura E, Miyazaki M (1997) Induction of chymase that forms angiotensin II in the monkey atherosclerotic aorta. FEBS Lett 412:86–90CrossRefPubMedGoogle Scholar
  158. Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W, Dzavik V, Taylor D, Yokoyama S, Montague TJ (2000) Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 102:1748–1754PubMedGoogle Scholar
  159. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators (1993) Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 342:821–828Google Scholar
  160. The ALLHAT Collaborative Research Group (2002) Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 288:2981–2997Google Scholar
  161. The CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316:1429–1435Google Scholar
  162. The SOLVD Investigattors (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327:685–691Google Scholar
  163. Townsend RR, Zhao H (1994) Plasma renin activity and insulin sensitivity in normotensive subjects. Am J Hypertens 7:894–898PubMedGoogle Scholar
  164. Tummala PE, Chen XL, Sundell CL, Laursen JB, Hammes CP, Alexander RW, Harrison DG, Medford RM (1999) Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: A potential link between the renin-angiotensin system and atherosclerosis. Circulation 100:1223–1229PubMedGoogle Scholar
  165. Uehara Y, Urata H, Sasaguri M, Ideishi M, Sakata N, Tashiro T, Kimura M, Arakawa K (2000) Increased chymase activity in internal thoracic artery of patients with hypercholesterolemia. Hypertension 35:55–60PubMedGoogle Scholar
  166. UK Prospective Diabetes Study Group (1998) Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317:713–720Google Scholar
  167. Vaughan DE (2002) Angiotensin and vascular fibrinolytic balance. Am J Hypertens 15:3S–8SCrossRefPubMedGoogle Scholar
  168. Veerasingham SJ, Raizada MK (2003) Brain renin-angiotensin system dysfunction in hypertension: recent advances and perspectives. Br J Pharmacol 139:191–202CrossRefPubMedGoogle Scholar
  169. Viswanathan M, Stromberg C, Seltzer A, Saavedra JM (1992) Balloon angioplasty enhances the expression of angiotensin II AT1 receptors in neointima of rat aorta. J Clin Invest 90:1707–1712PubMedGoogle Scholar
  170. Wagenaar LJ, van Boven AJ, van der Wal AC, Amoroso G, Tio RA, van der Loos CM, Becker AE, van Gilst WH (2003) Differential localisation of the renin-angiotensin system in de-novo lesions and in-stent restenotic lesions in in-vivo human coronary arteries. Cardiovasc Res 59:980–987CrossRefPubMedGoogle Scholar
  171. Wang CH, Li SH, Weisel RD, Fedak PW, Dumont AS, Szmitko P, Li RK, Mickle DA, Verma S (2003) C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation 107:1783–1790CrossRefPubMedGoogle Scholar
  172. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Bohm M, Meinertz T, Munzel T (1999) Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 99:2027–2033PubMedGoogle Scholar
  173. Wassmann S, Laufs U, Baumer AT, Muller K, Ahlbory K, Linz W, Itter G, Rosen R, Bohm M, Nickenig G (2001) HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37:1450–1457PubMedGoogle Scholar
  174. Weiss D, Kools JJ, Taylor WR (2001) Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice. Circulation 103:448–454PubMedGoogle Scholar
  175. Wheatcroft SB, Williams IL, Shah AM, Kearney MT (2003) Pathophysiological implications of insulin resistance on vascular endothelial function. Diabet Med 20:255–268CrossRefPubMedGoogle Scholar
  176. Williams B, Baker AQ, Gallacher B, Lodwick D (1995) Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells. Hypertension 25:913–917PubMedGoogle Scholar
  177. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ (2003) A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 348:583–592CrossRefPubMedGoogle Scholar
  178. Wolny A, Clozel JP, Rein J, Mory P, Vogt P, Turino M, Kiowski W, Fischli W (1997) Functional and biochemical analysis of angiotensin II-forming pathways in the human heart. Circ Res 80:219–227PubMedGoogle Scholar
  179. Wong J, Rauhoft C, Dilley RJ, Agrotis A, Jennings GL, Bobik A (1997) Angiotensin-converting enzyme inhibition abolishes medial smooth muscle PDGF-AB biosynthesis and attenuates cell proliferation in injured carotid arteries: relationships to neointima formation. Circulation 96:1631–1640PubMedGoogle Scholar
  180. Wu L, Iwai M, Nakagami H, Li Z, Chen R, Suzuki J, Akishita M, de Gasparo M, Horiuchi M (2001) Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury. Circulation 104:2716–2721PubMedGoogle Scholar
  181. Xu J, Carretero OA, Liu YH, Shesely EG, Yang F, Kapke A, Yang XP (2002) Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension 40:244–250CrossRefPubMedGoogle Scholar
  182. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P (2000a) Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:154–160CrossRefPubMedGoogle Scholar
  183. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000b) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145–153CrossRefPubMedGoogle Scholar
  184. Zhuo J, Moeller I, Jenkins T, Chai SY, Allen AM, Ohishi M, Mendelsohn FA (1998) Mapping tissue angiotensin-converting enzyme and angiotensin AT1, AT2 and AT4 receptors. J Hypertens 16:2027–2037CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • A. Dendorfer
    • 1
  • P. Dominiak
    • 1
  • H. Schunkert
    • 1
  1. 1.Medizinische Klinik IIUniversitätsklinikum Schleswig-HosteinLübeckGermany

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