The Renin-Angiotensin System in Diabetic Cardiovascular Complications

  • Edward P. Feener
Part of the Contemporary Cardiology book series (CONCARD)


The renin-angiotensin system (RAS) plays an integral role in blood pressure regulation and also exerts a diverse range of direct effects on vascular homeostasis. Reports from a growing number of clinical trials have demonstrated that suppression of the RAS by angiotensin-converting enzyme (ACE) inhibitors reduces the onset and/or progression of certain renal (1–7), retinal (8,9), and cardiovascular (5,9–12) complications of diabetes mellitus. These findings, along with a considerable body of experimental evidence, suggest that the RAS contributes to the etiology of vascular dysfunction and disease caused by diabetes.


Nitric Oxide Diabetic Nephropathy Angiotensin Converting Enzyme Candesartan Cilexetil Diabetic Vascular Complication 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456–1462.PubMedGoogle Scholar
  2. 2.
    Laffel L, McGill JB, Gan DJ. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American Microalbuminuria Study Group. Am J Med 1995;99:497–504.PubMedGoogle Scholar
  3. 3.
    The Microalbuminuria Captopril Study Group. Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. Diabetologia 1996;39:587–593.Google Scholar
  4. 4.
    Mathiesen ER, Hommel E, Hansen HP, Smidt UM, Parving HH. Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. BMJ 1999;319:24–25.PubMedGoogle Scholar
  5. 5.
    Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICROHOPE substudy. Lancet 2000;355:253–259.Google Scholar
  6. 6.
    TheEUCLIDStudyGroup.Randomisedplacebo-controlledtrialoflisinoprilinnormotensivepatients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997;349:1787– 1792.Google Scholar
  7. 7.
    Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998;128:982–988.PubMedGoogle Scholar
  8. 8.
    Chaturvedi N, Sjolle AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet 1998;351:28–31.PubMedGoogle Scholar
  9. 9.
    UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703–713.Google Scholar
  10. 10.
    Zuanetti G, Latini R, Maggioni AP, Franzosi MG, Santoro L, Tognoni G. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction data from the GISSI-3 study. Circulation 1997;96:4239–4245.PubMedGoogle Scholar
  11. 11.
    Gustafsson I, Torp-Pedersen C, Kober L, Gustafs son F, Hildebrandt P. Effect of the angiotensinconverting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. Trace Study Group. J Am Coll Cardiol 1999; 34:83–89.PubMedGoogle Scholar
  12. 12.
    Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597–603.PubMedGoogle Scholar
  13. 13.
    Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II- forming enzyme in the human heart. J Biol Chem 1990;265:22,348–22,357.Google Scholar
  14. 14.
    Owen CA, Campbell EJ. Angiotensin II generation at the cell surface of activated neutrophils: novel cathepsin G-mediated catalytic activity that is resistant to inhibition. J Immunol1998;160:1436– 1443.Google Scholar
  15. 15.
    Liao Y, Husain A. The chymase-angiotensin system in humans: biochemistry, molecular biology and potential role in cardiovascular diseases. Can J Cardiol 1995;11(Suppl F):13F–19F.Google Scholar
  16. 16.
    Zisman LS, Abraham WT, Meixell GE, et al. Angiotensin II formation in the intact human heart. J Clin Invest 1995;96:1490–1498.PubMedGoogle Scholar
  17. 17.
    Dzau VJ. Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J 1998;19(Suppl J):J2–J6.Google Scholar
  18. 18.
    Takai S, Shiota N, Kobayashi S, Matsumura E, Miyazaki M. Induction of chymase that forms angiotensin II in the monkey atherosclerotic aorta. FEBS Lett 1997;412:86–90.PubMedGoogle Scholar
  19. 19.
    Song K, Shiota N, Takai S, et al. Induction of angiotensin converting enzyme and angiotensin II receptors in the atherosclerotic aorta of high-cholesterol fed cynomolgus monkeys. Atherosclerosis 1998; 138:171–182.PubMedGoogle Scholar
  20. 20.
    Healy DP, Song L. Kidney aminopeptidase A and hypertension, part I: spontaneously hypertensive rats. Hypertension 1999;33:740–745.PubMedGoogle Scholar
  21. 21.
    Reaux A, Fournie-Zaluski MC, David C, et al. Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci USA 1999;96:13,415–13,420.Google Scholar
  22. 22.
    Patel JM, Martens JR, Li YD, Gelband CH, Raizada MK, Block ER. Angiotensin IV receptor-mediated activation of lung endothelial NOS is associated with vasorelaxation. Am J Physiol 1998;275:L1061–L1068.Google Scholar
  23. 23.
    Coleman JK, Krebs LT, Hamilton TA, et al. Autoradiographic identification of kidney angiotensin IV binding sites and angiotensin IV-induced renal cortical blood flow changes in rats. Peptides 1998;19: 269–277.PubMedGoogle Scholar
  24. 24.
    Tan F, Morris PW, Skidgel RA, Erdos EG. Sequencing and cloning of human prolylcarboxypeptidase (angiotensinase C). Similarity to both serine carboxypeptidase and prolylendopeptidase families. J Biol Chem 1993;268:16,631–16,638.Google Scholar
  25. 25.
    Freeman EJ, Chisolm GM, Ferrario CM, Tallant EA. Angiotensin-(1–7) inhibits vascular smooth muscle cell growth. Hypertension 1996;28:104–108.PubMedGoogle Scholar
  26. 26.
    Benter IF, Ferrario CM, Morris M, Diz DI. Antihypertensive actions of angiotensin-(1–7) in spontaneously hypertensive rats. Am J Physiol 1995;269:H313–H319.Google Scholar
  27. 27.
    Ardaillou R. Angiotensin II receptors. J Am Soc Nephrol 1999;10(Suppl 11):S3(–s39.Google Scholar
  28. 28.
    Black HR, Graff A, Shute D, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy, tolerability and safety compared to an angiotensin-converting enzyme inhibitor, lisinopril. J Hum Hypertens 1997;11:483–489.PubMedGoogle Scholar
  29. 29.
    McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999;100:1056–1064.PubMedGoogle Scholar
  30. 30.
    Kim S, Wanibuchi H, Hamaguchi A, Miura K, Yamanako S, Iwao H. Angiotensin blockade improves cardiac and renal complications of type II diabetic rats. Hypertension 1997;30:1054–1061.PubMedGoogle Scholar
  31. 31.
    Hope S, Brecher P, Chobanian AV. Comparison of the effects of AT1 receptor blockade and angiotensin converting enzyme inhibition on atherosclerosis. Am J Hypertens 1999;12:28–34.PubMedGoogle Scholar
  32. 32.
    Goodfield NE, Newby DE, Ludlam CA, Flapan AD. Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 1999;99:2983–2985.PubMedGoogle Scholar
  33. 33.
    Horiuchi M, Akishita M, Dzau VJ. Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension 1999;33:613–621.PubMedGoogle Scholar
  34. 34.
    Unger T. Neurohormonal modulation in cardiovascular disease. Am Heart J 2000;139:S2–S8.Google Scholar
  35. 35.
    Oliverio MI, Kim HS, Ito M, et al. Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II. Proc Natl Acad Sci USA 1998;95:15,496–15,501.Google Scholar
  36. 36.
    Tsuchida S, Matsusaka T, Chen X, et al. Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes. J Clin Invest 1998;101:755–760.PubMedGoogle Scholar
  37. 37.
    WeirMR,DzauVJ.Therenin-angiotensin-aldosteronesystem:aspecifictargetforhypertensionmanagement. Am J Hypertens 1999;12:205S–213S.Google Scholar
  38. 38.
    Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev 1998;78:583–686.Google Scholar
  39. 39.
    Mehler PS, Jeffers BW, Estacio R, Schrier RW. Associations of hypertension and complications in non-insulin-dependent diabetes mellitus. Am J Hypertens 1997;10:152–161.PubMedGoogle Scholar
  40. 40.
    UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317:713–720.Google Scholar
  41. 41.
    Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 1986;77: 1925–1930.PubMedGoogle Scholar
  42. 42.
    Imanishi M, Yoshioka K, Konishi Y, et al. Glomerular hypertension as one cause of albuminuria in type II diabetic patients. Diabetologia 1999;42:999–1005.PubMedGoogle Scholar
  43. 43.
    Imanishi M, Yoshioka K, Okumura M, et al. Mechanism of decreased albuminuria caused by angiotensin converting enzyme inhibitor in early diabetic nephropathy. Kidney Int Suppl1997;63: S 198–S200.Google Scholar
  44. 44.
    Anderson S, Rennke HG, Garcia DL, Brenner BM. Short and long term effects of antihypertensive therapy in the diabetic rat. Kidney Int 1989;36:526–536.PubMedGoogle Scholar
  45. 45.
    Chen KD, Li YS, Kim M, et al. Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J Biol Chem 1999;274:18,393–18,400.Google Scholar
  46. 46.
    Hoyer J, Kohler R, Haase W, Distler A. Up-regulation of pressure-activated Ca(2+)-permeable cation channel in intact vascular endothelium of hypertensive rats. Proc Natl Acad Sci USA 1996;93:11,253–11,258.Google Scholar
  47. 47.
    Hamada K, Takuwa N, Yokoyama K, Takuwa Y. Stretch activates Jun N-terminal kinase/stress-activated protein kinase in vascular smooth muscle cells through mechanisms involving autocrine ATP stimulation of purinoceptors. J Biol Chem 1998;273:6334–6340.PubMedGoogle Scholar
  48. 48.
    Ohno M, Cooke JP, Dzau VJ, Gibbons GH. Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production. Modulation by potassium channel blockade. J Clin Invest 1995;95:1363–1369.Google Scholar
  49. 49.
    Cooper ME, Rumble J, Komers R, He-Cheng D, Jandeleit K, Sheung-To C. Diabetes-associated mesenteric vascular hypertrophy is attenuated by angiotensin-converting-enzyme inhibition. Diabetes 1994;43:1221–1228.PubMedGoogle Scholar
  50. 50.
    Schieffer B, Wirger A, Meybrunn M, et al. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation 1994;89:2273–2282.PubMedGoogle Scholar
  51. 51.
    de las H, Aragoncillo P, Maeso R, et al. AT(1) receptor antagonism reduces endothelial dysfunction and intimal thickening in atherosclerotic rabbits. Hypertension 1999;34:969–975.Google Scholar
  52. 52.
    Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation 1996;94:2756–2767.PubMedGoogle Scholar
  53. 53.
    Yang BC, Phillips MI, Mohuczy D, Meng H, Shen L, Mehta P, Mehta JL. Increased angiotensin II type 1 receptor expression in hypercholesterolemic atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 1998;18:1433–1439.PubMedGoogle Scholar
  54. 54.
    Keidar S, Attias J, Heinrich R, Coleman R, Aviram M. Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis. Atherosclerosis 1999; 146:249–257.Google Scholar
  55. 55.
    Napoleone E, Di Santo A, Camera M, Tremoli E, Lorenzet R. Angiotensin-converting enzyme inhibitors downregulate tissue factor synthesis in monocytes. Circ Res 2000;86:139–143.PubMedGoogle Scholar
  56. 56.
    Yanagitani Y, Rakugi H, Okamura A, et al. Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. Hypertension 1999;33:335–339.PubMedGoogle Scholar
  57. 57.
    Al-Merani SA, Brooks DP, Chapman BJ, Munday KA. The half-lives of angiotensin II, angiotensin II-amide, angiotensin III, Sarl-Ala8-angiotensin II and renin in the circulatory system of the rat. J Physiol (Lond) 1978;278:471–490.Google Scholar
  58. 58.
    Chapman BJ, Brooks DP, Munday KA. Half-life of angiotensin II in the conscious and barbiturateanaesthetized rat. Br J Anaesth 1980;52:389–393.PubMedGoogle Scholar
  59. 59.
    Torlone E, Britta M, Rambotti AM, et al. Improved insulin action and glycemic control after long-term angiotensin-converting enzyme inhibition in subjects with arterial hypertension and type II diabetes. Diabetes Care 1993;16:1347–1355.PubMedGoogle Scholar
  60. 60.
    Valensi P, Derobert E, Genthon R, Riou JP. Effect of ramipril on insulin sensitivity in obese patients. Diabetes Metab 1996;22:197–200.PubMedGoogle Scholar
  61. 61.
    Herings RM, de Boer A, Stricker BH, Leufkens HG, Porsius A. Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme. Lancet 1995;345:1195.PubMedGoogle Scholar
  62. 62.
    Richey JM, Ader M, Moore D, Bergman RN. Angiotensin II induces insulin resistance independent of changes in interstitial insulin. Am J Physiol 1999;277:E920–E926.Google Scholar
  63. 63.
    Folli F, Kahn CR, Hansen H, Bouchie JL, Feener EP. Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. J Clin Invest 1997;100:2158–2169.PubMedGoogle Scholar
  64. 64.
    Velloso LA, Folli F, Sun XJ, White MF, Saad MJA, Kahn CR. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci USA 1996;93:12,490–12,495.Google Scholar
  65. 65.
    Galletti F, Strazzullo P, Capaldo B, et al. Controlled study of the effect of angiotensin converting enzyme inhibition versus calcium-entry blockade on insulin sensitivity in overweight hypertensive patients: Trandolapril Italian Study (TRIS). J Hypertens 1999;17:439–445.PubMedGoogle Scholar
  66. 66.
    Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P. Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients. Br J Clin Pharmacol 1998;46:467–471.PubMedGoogle Scholar
  67. 67.
    Bonora E, Targher G, Alberiche M, et al. Effect of chronic treatment with lacidipine or lisinopril on intracellular partitioning of glucose metabolism in type 2 diabetes mellitus. J Clin Endocrinol Metab 1999;84:1544–1550.PubMedGoogle Scholar
  68. 68.
    Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000;52:11–34.PubMedGoogle Scholar
  69. 69.
    Andersen S, Tarnow L, Rossing P, Hansen BV, Parving HH. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int 2000;57:601–606.PubMedGoogle Scholar
  70. 70.
    Kim S, Wanibuchi H, Hamaguchi A, Miura K, Yamanaka S, Iwao H. Angiotensin blockade improves cardiac and renal complications of type II diabetic rats. Hypertension 1997;30:1054–1061.PubMedGoogle Scholar
  71. 71.
    Remuzzi A, Perico N, Amuchastegui CS, et al. Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol 1993;4:40–49.PubMedGoogle Scholar
  72. 72.
    Cordonnier DJ, Pinel N, Barro C, et al. Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group. J Am Soc Nephrol 1999;10:1253–1263.PubMedGoogle Scholar
  73. 73.
    Nankervis A, Nicholls K, Kilmartin G, Allen P, Ratnaike S, Martin FI. Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study. Metabolism 1998;47:12–15.PubMedGoogle Scholar
  74. 74.
    Rudberg S, Osterby R, Bangstad HJ, Dahlquist G, Persson B. Effect of angiotensin converting enzyme inhibitor or beta blocker on glomerular structural changes in young microalbuminuric patients with type I (insulin-dependent) diabetes mellitus. Diabetologia 1999;42:589–595.PubMedGoogle Scholar
  75. 75.
    Allen TJ, Cao Z, Youssef S, Hulthen UL, Cooper ME. Role of angiotensin II and bradykinin in experimental diabetic nephropathy. Functional and structural studies. Diabetes 1997;46:1612–1618.PubMedGoogle Scholar
  76. 76.
    Bennett PH, Haffner S, Kasiske BL, et al. Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 1995;25:107–112.PubMedGoogle Scholar
  77. 77.
    Patel V, Rassam SM, Chen HC, Jones M, Kohner EM. Effect of angiotensin-converting enzyme inhibition with perindopril and beta-blockade with atenolol on retinal blood flow in hypertensive diabetic subjects. Metabolism 1998;47:28–33.PubMedGoogle Scholar
  78. 78.
    Domanski MJ, Exner DV, Borkowf CB, Geller NL, Rosenberg Y, Pfeffer MA. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta- analysis of randomized clinical trials. J Am Coll Cardiol 1999;33:598–604.PubMedGoogle Scholar
  79. 79.
    Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450–1456.PubMedGoogle Scholar
  80. 80.
    Diabetes mellitus: a major risk factor for cardiovascular disease. A joint editorial statement by the American Diabetes Association; The National Heart, Lung, and Blood Institute; The Juvenile Diabetes Foundation International; The National Institute of Diabetes and Digestive and Kidney Diseases; and The American Heart Association. Circulation 1999;100:1132–1133.Google Scholar
  81. 81.
    Estacio RO, Schrier RW. Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial. Am J Cardiol 1998;82:9R–14R.Google Scholar
  82. 82.
    Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998;338:645–652.PubMedGoogle Scholar
  83. 83.
    Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–153.PubMedGoogle Scholar
  84. 84.
    Thamer M, Ray NF, Taylor T. Association between antihypertensive drug use and hypoglycemia: a case-control study of diabetic users of insulin or sulfonylureas. Clin Ther 1999;21:1387–1400.PubMedGoogle Scholar
  85. 85.
    Morris AD, Boyle DI, McMahon AD, et al. ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes. DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside, Scotland. Medicines Monitoring Unit. Diabetes Care 1997;20:1363–1367.PubMedGoogle Scholar
  86. 86.
    Henriksen EJ, Jacob S, Kinnick TR, Youngblood EB, Schmit MB, Dietze GJ. ACE inhibition and glucose transport in insulin resistant muscle: roles of bradykinin and nitric oxide. Am J Physiol 1999; 277:R332–R336.Google Scholar
  87. 87.
    Henriksen EJ, Jacob S. Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats. Metabolism 1995;44:267–272.PubMedGoogle Scholar
  88. 88.
    Caldiz CI, de Cingolani GE. Insulin resistance in adipocytes from spontaneously hypertensive rats: effect of long-term treatment with enalapril and losartan. Metabolism 1999;48:1041–1046.PubMedGoogle Scholar
  89. 89.
    Jacob S, Henriksen EJ, Fogt DL, Dietze GJ. Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle. Metabolism 1996;45:535–541.PubMedGoogle Scholar
  90. 90.
    Henriksen EJ, Jacob S, Fogt DL, Dietze GJ. Effect of chronic bradykinin administration on insulin action in an animal model of insulin resistance. Am J Physiol 1998;275:R40–R45.Google Scholar
  91. 91.
    Trenkwalder P. Effects of candesartan cilexetil on glucose homeostasis. Multicenter Study Group. Basic Res Cardiol 1998;93(Suppl 2):140–144.PubMedGoogle Scholar
  92. 92.
    TrenkwalderP,DahlK,LehtovirtaM,MulderH.Antihypertensivetreatmentwithcandesartancilexetil does not affect glucose homeostasis or serum lipid profile in patients with mild hypertension and type II diabetes. Blood Press 1998;7:170–175.Google Scholar
  93. 93.
    Tillmann HC, Walker RJ, Lewis-Barned NJ, Edwards EA, Robertson MC. A long-term comparison between enalapril and captopril on insulin sensitivity in normotensive non-insulin dependent diabetic volunteers. J Clin Pharm Ther 1997;22:273–278.PubMedGoogle Scholar
  94. 94.
    New JP, Bilous RW, Walker M. Insulin sensitivity in hypertensive type 2 diabetic patients after 1 and 19 days’ treatment with trandolapril. Diabetes Med 2000;17:134–140.Google Scholar
  95. 95.
    Nakagawa H, DaiharaM, Tamakawa H, Nozue T, Kawahara K. Effects of quinapril and losartan on insulin sensitivity in genetic hypertensive rats with different metabolic abnormalities. J Cardiovasc Pharmacol 1999;34:28–33.PubMedGoogle Scholar
  96. 96.
    Carvalho CR, Thirone AC, Gontijo JA, Velloso LA, Saad MJ. Effect of captopril, losartan, and bradykinin on early steps of insulin action. Diabetes 1997;46:1950–1957.PubMedGoogle Scholar
  97. 97.
    Uehara Y, Hirawa N, Numabe A, et al. Angiotensin-converting enzyme inhibition delays onset of glucosuria with regression of renal injuries in genetic rat model of non-insulin-dependent diabetes mellitus. J Cardiovasc Pharmacol Ther 1998;3:327–336.PubMedGoogle Scholar
  98. 98.
    Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 2000;342:905–912.PubMedGoogle Scholar
  99. 99.
    Campbell DJ, Kelly DJ, Wilkinson-Berka JL, Cooper ME, Skinner SL. Increased bradykinin and “normal” angiotensin peptide levels in diabetic Sprague-Dawley and transgenic (mRen-2)27 rats. Kidney Int 1999;56:211–221.PubMedGoogle Scholar
  100. 100.
    Vallon V, Wead LM, Blantz RC. Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats: effect of sodium and saltrestriction. J Am Soc Nephrol1995;5:1761–1767.Google Scholar
  101. 101.
    Nakayama T, Izumi Y, Soma M, Kanmatsuse K. Adrenal renin-angiotensin-aldosterone system in streptozotocin-diabetic rats. Horm Metab Res 1998;30:12–15.PubMedGoogle Scholar
  102. 102.
    Cronin CC, Barry D, Crowley B, Ferriss JB. Reduced plasma aldosterone concentrations in randomly selected patients with insulin-dependent diabetes mellitus. Diabetes Med 1995;12:809–815.Google Scholar
  103. 103.
    Price DA, Porter LE, Gordon M, et al. The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol 1999;10:2382–2391.PubMedGoogle Scholar
  104. 104.
    Anderson S, Jung FF, Inglefinger J. Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. Am J Physiol 1993;265:F477–F486.Google Scholar
  105. 105.
    Brown L, Wall D, Marchant C, Sernia C. Tissue-specific changes in angiotensin II receptors in streptozotocin-diabetic rats. J Endocrinol 1997;154:355–362.PubMedGoogle Scholar
  106. 106.
    Sechi LA, Griffin CA, Schambelan M. The cardiac renin-angiotensin system in STZ-induced diabetes. Diabetes 1994;43:1180–1184.PubMedGoogle Scholar
  107. 107.
    Erman A, van Dyk DJ, Chen-Gal B, Giler ID, Rosenfeld JB, Boner G. Angiotensin converting enzyme activity in the serum, lung and kidney of diabetic rats. Eur J Clin Invest 1993;23:615–620.PubMedGoogle Scholar
  108. 108.
    Correa-Rotter R, Hostetter TH, Rosenberg ME. Renin and angiotensinogen gene expression in experimental diabetes mellitus. Kidney Int 1992;41:796–804.PubMedGoogle Scholar
  109. 109.
    CassisLA.Downregulationoftherenin-angiotensinsysteminstreptozotocin-diabeticrats.AmPhysiol Soc 1992;262:E105–E109.Google Scholar
  110. 110.
    Jost-Vu E, Horton R, Antonipillai I. Altered regulation of renin secretion by insulin like growth factors and angiotensin II in diabetic rats. Diabetes 1992;41:1100–1105.PubMedGoogle Scholar
  111. 111.
    HarkerCT,O’DonnellMP,KasiskeBL,KeaneWF,KatzSA.Therenin-angiotensinsysteminthetype II diabetic obese Zucker rat. J Am Soc Nephrol 1993;4:1354–1361.Google Scholar
  112. 112.
    Schunkert H, Ingelfinger JR, Jacob H, Jackson B, Bouyounes B, Dzau VJ. Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II. Am J Physiol 1992; 263:E863–E869.Google Scholar
  113. 113.
    Drury PL, Smith GM, Ferriss JB. Increased vasopressor responsiveness to angiotensin II in type 1 (insulin-dependent) diabetic patients without complications. Diabetologia 1984;27:174–179.PubMedGoogle Scholar
  114. 114.
    Kennefick TM, Oyama TT, Thompson MM, Vora JP, Anderson S. Enhanced renal sensitivity to angiotensin actions in diabetes mellitus in the rat. Am J Physiol 1996;271:F595–F602.Google Scholar
  115. 115.
    Trevisan R, Bruttomesso D, Vedovato M, et al. Enhanced responsiveness of blood pressure to sodium intake and to angiotensin II is associated with insulin resistance in IDDM patients with microalbuminuria. Diabetes 1998;47:1347–1353.PubMedGoogle Scholar
  116. 116.
    Christlieb AR, Janka HU, Kraus B, et al. Vascular reactivity to angiotensin II and to norepinephrine in diabetic subjects. Diabetes 1976;25:268–274.PubMedGoogle Scholar
  117. 117.
    Wagner J, Gehlen F, Ciechanowicz A, Ritz E. Angiotensin II receptor type 1 gene expression in human glomerulonephritis and diabetes mellitus. J Am Soc Nephrol 1999;10:545–551.PubMedGoogle Scholar
  118. 118.
    Bouchie JL, Hansen H, Feener EP. Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system. Arterioscler Thromb Vasc Biol 1998;18:1771–1779.PubMedGoogle Scholar
  119. 119.
    Yoshizumi M, Tsuji H, Nishimura H, et al. Atrial natriuretic peptide inhibits the expression of tissue factor and plasminogen activator inhibitor 1 induced by angiotensin II in cultured rat aortic endothelial cells. Thromb Haemost 1998;79:631–634.PubMedGoogle Scholar
  120. 120.
    Dubey RK, Jackson EK, Luscher TF. Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cell. J Clin Invest 1995;96:141–149.PubMedGoogle Scholar
  121. 121.
    Pollman MJ, Yamada T, Horiuchi M, Gibbons GH. Vasoactive substances regulate vascular smooth muscle cell apoptosis. Circ Res 1996;79:748–756.PubMedGoogle Scholar
  122. 122.
    Takizawa T, Gu M, Chobanian AV, Brecher P. Effect of nitric oxide on DNA replication induced by angiotensin II in rat cardiac fibroblasts. Hypertension 1997;30:1035–1040.PubMedGoogle Scholar
  123. 123.
    Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510–2516.PubMedGoogle Scholar
  124. 124.
    Williams SB, Cusco JA, Roddy M-A, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27: 567–574.PubMedGoogle Scholar
  125. 125.
    Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343–1346.PubMedGoogle Scholar
  126. 126.
    Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641–644.PubMedGoogle Scholar
  127. 127.
    Schunkert H, Hense H-W, Holmer SR, et al. Association between a deletion polymorphism of the angiotensin- converting-enzyme gene and left ventricular hypertrophy. N Engl J Med 1994;330:1634–1638.PubMedGoogle Scholar
  128. 128.
    Mattu RK, Needham EW, Galton DJ, Frangos E, Clark AJ, Caulfield M. A DNA variant at the angiotensin-converting enzyme gene locus associate with coronary artery disease in the Caerphilly Heart Study. Circulation 1995;91:270–274.PubMedGoogle Scholar
  129. 129.
    Lindpaintner K, Lee M, Larson MG, et al. Absence of association or genetic linkage between the angiotensin- converting-enzyme gene and left ventricular mass. N Engl J Med 1996;334:1023–1028.PubMedGoogle Scholar
  130. 130.
    Fujimura T, Yokota M, Kato S, et al. Lack of association of angiotensin converting enzyme gene polymorphism or serum enzyme activity with coronary artery disease in Japanese subjects. Am J Hypertens 1997;10:1384–1390.PubMedGoogle Scholar
  131. 131.
    Lindpaintner K, Pfeffer MA, Kreutz R, et al. A prospective evaluation of an angiotensin-convertingenzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995;332:706–711.PubMedGoogle Scholar
  132. 132.
    Ruiz J, Blanche H, Cohen N, et al. Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is strongly associated with coronary heart disease in non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 1994;91:3662–3665.PubMedGoogle Scholar
  133. 133.
    Estacio RO, Jeffers BW, Havranek EP, Krick D, Raynolds M, Schrier RW. Deletion polymorphism of the angiotensin converting enzyme gene is associated with an increase in left ventricular mass in men with type 2 diabetes mellitus. Am J Hypertens 1999;12:637–642.PubMedGoogle Scholar
  134. 134.
    Kimura H, Gejyo F, Suzuki Y, Suzuki S, Miyazaki R, Arakawa M. Polymorphisms of angiotensin converting enzyme and plasminogen activator inhibitor-1 genes in diabetes and macroangiopathy. Kidney Int 1998;54:1659–1669.PubMedGoogle Scholar
  135. 135.
    Huang XH, Rantalaiho V, Wirta O, et al. Angiotensin-converting enzyme gene polymorphism is associated with coronary heart disease in non-insulin-dependent diabetic patients evaluated for 9 years. Metabolism 1998;47:1258–1262.PubMedGoogle Scholar
  136. 136.
    Sagnella GA, Rothwell MJ, Onipinla AK, Wicks PD, Cook DG, Cappuccio FP. A population study of ethnic variations in the angiotensin-converting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism. J Hypertens 1999;17:657–664.PubMedGoogle Scholar
  137. 137.
    Soubrier F, Nadaud S, Williams TA. Angiotensin I converting enzyme gene: regulation, polymorphism and implications in cardiovascular diseases. Eur Heart J 1994;15:24–29.PubMedGoogle Scholar
  138. 138.
    Kim DK, Kim JW, Kim S, et al. Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 1997;17: 3242–3247.PubMedGoogle Scholar
  139. 139.
    Matsubara Y, Hayakawa T, Tsuda T, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with plasma antigen levels of plasminogen activator inhibitor-1 in healthy Japanese population. Blood Coagul Fibrinolysis 2000;11:115–120.PubMedGoogle Scholar
  140. 140.
    Jiang ZY, Lin YW, Clemont A, et al. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999;104:447–457.PubMedGoogle Scholar
  141. 141.
    Abe H, Yamada N, Kamata K, et al. Hypertension, hypertriglyceridemia, and impaired endotheliumdependent vascular relaxation in mice lacking insulin receptor substrate-1. J Clin Invest 1998;101: 1784–1788.PubMedGoogle Scholar
  142. 142.
    Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. J Clin Invest 1996;98:894–898.PubMedGoogle Scholar
  143. 143.
    Zeng G, Nystrom FH, Ravichandran LV, et al. 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.PubMedGoogle Scholar
  144. 144.
    Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 2000;275:9047–9054.PubMedGoogle Scholar
  145. 145.
    Schmitz U, Ishida T, Ishida M, et al. Angiotensin II stimulates p21-activated kinase in vascular smooth muscle cells: role in activation of JNK. Circ Res 1998;82:1272–1278.PubMedGoogle Scholar
  146. 146.
    Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996;97:2601–2610.PubMedGoogle Scholar
  147. 147.
    Kuboki K, Jiang ZY, Takahara N, et al. 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
  148. 148.
    Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endotheliumdependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996;97: 22–28.PubMedGoogle Scholar
  149. 149.
    Arcaro G, Zenere BM, Saggiani F, et al. ACE inhibitors improve endothelial function in type 1 diabetic patients with normal arterial pressure and microalbuminuria. Diabetes Care 1999;22:1536–1542.PubMedGoogle Scholar
  150. 150.
    O’ Driscoll G, Green D, Rankin J, Stanton K, Taylor R. Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest 1997;100: 678–684.Google Scholar
  151. 151.
    O’Driscoll G, Green D, Maiorana A, Stanton K, Colreavy F, Taylor R. Improvement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1999;33:1506–1511.PubMedGoogle Scholar
  152. 152.
    Lang D, Mosfer SI, Shakesby A, Donaldson F, Lewis MJ. Coronary microvascular endothelial cell redox state in left ventricular hypertrophy: the role of angiotensin II. Circ Res 2000;86:463–469.PubMedGoogle Scholar
  153. 153.
    McFarlane R, McCredie RJ, Bonney MA, et al. Angiotensin converting enzyme inhibition and arterial endothelial function in adults with Type 1 diabetes mellitus. Diabetes Med 1999;16:62–66.Google Scholar
  154. 154.
    Mullen MJ, Clarkson P, Donald AE, et al. Effect of enalapril on endothelial function in young insulindependent diabetic patients: a randomized, double-blind study. J Am Coll Cardiol1998;31:133(–1335.Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Edward P. Feener

There are no affiliations available

Personalised recommendations