Abstract
The renin-angiotensin-aldosterone system (RAAS) exerts a principal influence in maintaining vascular tone, optimal salt and water homeostasis, and forward cardiac output in human beings. Overactivity of the RAAS can lead to pathologic consequences in states of diabetic nephropathy, hypertension, renal artery stenosis, left ventricular hypertrophy, coronary atherosclerosis, myocardial infarction, and congestive heart failure. In addition to fluid and hemodynamic effects, the RAAS may have a critical role in the activation of the sympathetic nervous system, the progression of atherosclerosis, the dysregulation of endothelial function, and the inhibition of the fibrinolytic system. Accumulated basic and clinical evidence supports the use of inhibitors of the RAAS, including aldosterone antagonists, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, in treating hypertension, improving diabetic nephropathy, preventing or ameliorating congestive heart failure, and optimizing the prognosis after myocardial infarction. (J Nucl Cardiol 2003;10:184-96.)
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Skeggs LT, Dorer FE, Kahn JR, Lentz KE, Levine M. The biochemistry of the renin-angiotensin system and its role in hypertension. Am J Med 1976;60:737–48.
Erdos EG. Angiotensin I converting enzyme and the changes in our concepts through the years. Hypertension 1990;16:363–70.
Mitchell KD, Navar LG. The renin-angiotensin-aldosterone system in volume control. In: Paylis PH, editor. Bailliere’s clinical endocrinology and metabolism. 2nd ed. London: Bailliere Tindall; 1989. p. 393–430.
Dzau VJ. Cell biology and genetics of angiotensin in cardiovascular disease. J Hypertens 1994;12(Suppl 4):S3–10.
Muller DN, Luft FC. The renin-angiotensin system in the vessel wall. Basic Res Cardiol 1998;93(Suppl2):7–14.
Dzau VJ, Re R. Tissue angiotensin system in cardiovascular medicine: a paradigm shift? Circulation 1994;89:493–8.
Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens 1999;12:205S-13S.
Rosenberg ME, Smith LJ, Correa-Rotter R, Hostetter TH. The paradox of the renin-angiotensin system in chronic renal disease. Kidney Int 1994;45:403–10.
Johnston CI. Renin-angiotensin system: a dual tissue and hormonal system for cardiovascular control. J Hypertens Suppl 1992;10:S13–26.
Navar LG, Lewis L, Hymel A, Braam B, Mitchell KD. Tubular fluid concentrations and kidney contents of angiotensin I and II in anesthetized rats. J Am Soc Nephrol 1994;5:1153–8.
Navar LG, Harrison-Bernard LM, Imig JD, et al. Intrarenal angiotensin II generation and renal effects of AT1 receptor blockade. J Am Soc Nephrol 1999;10:S266–72.
Laragh JH, Angers M, Kelly WG, Lieberman S. Hypotensive agents and pressor substances: the effect of epinephrine, norepinephrine, angiotensin II, and others on the secretory rate of aldosterone in man. J Am Med Assoc 1960;174:234–40.
Garty H. Regulation of sodium permeability by aldosterone. Sem Nephrol 1992;12:24–9.
Wood AJJ. Angiotensin receptors and their antagonists. N Engl J Med 1996;334:1649–54.
Unger T, Culman J, Gohlke P. Angiotensin II receptor blockade and end-organ protection: pharmacological rationale and evidence. J Hypertens 1998;16:S3–9.
Duncan JA, Scholey JW, Miller JA. Angiotensin II type 1-receptor gene polymorphisms in humans: physiology and pathophysiology of the genotypes. Curr Opin Nephrol Hypertens 2001;10:111–66.
Siragy HM, Carey RM. Angiotensin type 2 receptors: potential importance in the regulation of blood pressure. Curr Opin Nephrol Hypertens 2001;10:99–103.
Tsutsami Y, Matsubara H, Masaki H, et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilatation. J Clin Invest 1999;104:925–35.
Arima S, Ito S. Angiotensin II type 2 receptors in the kidney: evidence for endothelial-cell-mediated renal vasodilatation. Nephrol Dial Transplant 2000;15:448–51.
Liu FY, Cogan MG. Angiotensin II stimulates early proximal bicarbonate absorption in the rat by decreasing cyclic adenosine monophosphate. J Clin Invest 1989;84:83–91.
Garvin JL. Angiotensin stimulates bicarbonate transport and Na+/K+ ATPase in rat proximal straight tubules. J Am Soc Nephrol 1991;1:1146–52.
Wang T, Giebisch G. Effects of AII on electrolyte transport in the early and late distal tubule in rat kidney. Am J Physiol 1996;271:F143–99.
Peti-Peterdi J, Warnock DG, Bell DP. Angiotensin II directly stimulates EnaC activity in the cortical collecting duct via AT1 receptors. J Am Soc Nephrol 2002;13:1131–5.
Wolf G. Angiotensin II as a mediator of tubulointerstitial injury. Nephrol Dial Transplant 2000;15:61–3.
Luft FC. Proinflammatory effects of angiotensin II and endothelin: targets for progression of cardiovascular and renal disease. Curr Opin Nephrol Hypertens 2002;11:59–66.
Tsuzuki S, Matoba T, Eguchi S, Inagami T. Angiotensin II type 2 receptor inhibits cell proliferation and activates tyrosine phosphatase. Hypertension 1996;28:916–8.
Juknevicius I, Segal Y, Kren S, et al. Aldosterone causes TGF-α expression [abstract]. J Am Soc Nephrol 2000;11:622A.
Hostetter TH, Rosenberg ME, Ibrahim HN, Juknevicius I. Aldosterone in renal disease. Curr Opin Nephrol Hypertens 2001;10:105–100.
Parving HH. Diabetic nephropathy: prevention and treatment. Kidney Int 2001;60:2041–55.
Ritz E, Stefanski A. Diabetic nephropathy in type II diabetes. Am J Kidney Dis 1996;27:167–94.
Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease: the modification of diet in renal disease study. Ann Intern Med 1995;123:754–62.
Jacobson HR. Chronic renal failure: pathophysiology. Lancet 1991;338:419–23.
Conlon PJ, O’Riordan E, Kalra PA. New insights into the epidemiology and clinical manifestations of atherosclerotic renovascular disease. Am J Kidney Dis 2000;35:573–87.
Suresh M, Laboi P, Mamtors H, Kalra PA. Relationship of renal dysfunction to proximal arterial disease severity in atherosclerotic renovascular disease. Nephrol Dial Transplant 2000;15:631–6.
Meyrier A, Hill GS, Simon P. Ischemic renal diseases: new insights into old entities. Kidney Int 1998;54:2–13.
Setaro JF, Saddler MC, Chen CC, et al. Simplified captopril renography in diagnosis and treatment of renal artery stenosis. Hypertension 1991;18:289–98.
Fommei E, Ghone S, Hilson AJ. Captopril radionuclide test in renovascular hypertension: a European multicentre study. Eur J Nucl Med 1991;90:30–40.
Hollifield JW, Sherman K, Zwagg RV, Shand DG. Proposed mechanisms of propranolol’s antihypertensive effect in essential hypertension. N Engl J Med 1976;295:68–73.
Lewis EJ, Hunsicker LG, Bain RP, Rhode RD. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456–62.
Maschio G, Alberti D, Janin G, et al. Effect of the angiotensinconverting- enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-converting Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996;334:939–45.
Brenner BM, Cooper ME, DeZeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9.
Parving HH, Lehnert H, Brochner-Mortensen J, et al. for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870–8.
Hilgers KF, Mann JFE. ACE inhibitors versus AT1 receptor antagonists in patients with chronic renal disease. J Am Soc Nephrol 2002;13:1100–8.
Lorell BH. Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and disease. Am J Cardiol 1999;83:H48–52.
Geisterfer AAT, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res 1988;62:749–56.
Schnee JM, Hsueh WA. Angiotensin II, adhesion, and cardiac fibrosis. Cardiovasc Res 2000;46:264–8.
Kajstura J, Cigola E, Malhotra A. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol 1997;29:859–70.
Aggarwal A, Brown KA, LeWinter MM. Diastolic dysfunction: pathophysiology, clinical features, and assessment with radionuclide methods. J Nucl Cardiol 2001;8:98–106.
Mandinov L, Eberli FR, Seiler C, Hess OM. Diastolic heart failure. Cardiovasc Res 2000;45:813–25.
Wachtell K, Smith G, Gerdts E, et al. Left ventricular filling patterns in patients with systemic hypertension and left ventricular hypertrophy (the LIFE Study). Am J Cardiol 2000;85:466- 72.
Setaro JF. The hypertensive heart: new observations and evolving therapeutic imperatives. J Clin Hypertens 2001;3:14–5.
Kawano H, Do YS, Kawano Y, et al. Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts. Circulation 2000; 101:1130–7.
Rocchini AP, Moorehead C, DeRemer S, Goodfriend TL, Ball DL. Hyperinsulinemia and the aldosterone and pressor responses to angiotensin II. Hypertension 1990;15:861–6.
Tuck M, Corry D, Trujillo A. Salt-sensitive blood pressure and exaggerated vascular reactivity in the hypertension of diabetes mellitus. Am J Med 1990;88:210–6.
Nakamura K, Fushimi K, Kouchi H, et al. Inhibitory effects of antioxidants on neonatal rat cardiac hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation 1998; 98:794–9.
Lang D, Mosfer SI, Shakesby A, Donaldson F, Lewis MJ. Coronary microvascular endothelial redox state in left ventricular hypertrophy. The role of angiotensin II. Circ Res 2000;86:463–9.
Reiss K, Capasso JM, Huang HE, et al. ANG II receptors, c-myc, and c-jun in myocytes after myocardial infarction and ventricular failure. Am J Physiol 1993;264:H760–9.
Meggs LG, Coupet J, Huang H, et al. Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats. Circ Res 1993;72:1149–62.
Asano K, Dutcher DL, Port JD, et al. Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium. Circulation 1997;95:1193–200.
Haywood GA, Gullestad L, Katsuya T, et al. AT1 and AT2 angiotensin receptor gene expression in human heart failure. Circulation 1997;95:1201–6.
White M, Racine N, Ducharme A, deChamplain J. therapeutic potential of angiotensin II receptor antagonists. Expert Opin Investig Drugs 2001;10:1687–701.
Saino A, Pomidossi G, Perondi R, et al. Modulation of sympathetic coronary vasoconstriction by cardiac renin-angiotensin system in human coronary heart disease. Circulation 2000;101:2277–833.
Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-defi- cient mice. J Clin Invest 2000;105:1605–12.
Kranzhofer R, Schmidt J, Pfeiffer CAH, et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1000;19:1623–9.
Kranzhofer R, Browatzki M, Schmidt J, Kubler W. Angiotensin II activates the proinflammatory transcription factor nuclear factor-kappa B in human monocytes. Biochem Biophys Res Commun 1999;257:826–8.
Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM. Angiotensin II induces monocyte chemoattractant protein-1 gene in rate vascular smooth muscle cells. Circ Res 1998;83:952–99.
Tummala PE, Chen XL, Sundell CL, et al. Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature. A potential link between the renin-angiotensin system and atherosclerosis. Circulation 1999;100:1223–9.
Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001;104:365–72.
Hernandez-Presa M, Bustos C, Ortego M, et al. Angiotensin converting enzyme inhibition prevents arterial nuclear factorkappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation 1997;95:1532–41.
Nakamura S, Nakamura I, Ma L, Vaughan DE, Fogo AB. Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo. Kidney Int 2000;58:251–9.
Pfeffer MA, Greaves SC, Arnold JMO, et al. Early vs delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction: the Healing and Early Afterload Reducing Therapy trial. Circulation 1997;95:2643–51.
Goodfield NER, 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;99:2983–5.
Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–53.
Vaughan DE. Fibrinolytic balance, the renin-angiotensin system, and atherosclerotic disease. Eur Heart J 1998;19(Suppl G):G9–12.
Fabre JE, Rivard A, Magner M, Silver M, Isner JM. Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo. Circulation 1999;99:3043–9.
Kjoller-Hansen L, Steffensen R, Grande P. The angiotensinconverting enzyme inhibition post revascularization study (APRES). J Am Coll Cardiol 2000;35:881–8.
Schiffrin EL, Deng LY. Relationship between small artery structure and systolic, diastolic, and pulse pressure in essential hypertension. J Hypertens 1999;17:381–7.
Andrews CO, Crim JW, Hartle DK. Angiotensin II binding in area postrema and nucleus tractus solitarius of SHR and WKY rats. Brain Res Bull 1993;32:419–24.
Wong PC, Bernard R, Timmermans PB. Effect of blocking angiotensin II receptor subtype on rat sympathetic nerve function. Hypertension 1992;19(6Pt 2):663–7.
Moreau P, D’Uscio LV, Shaw S, et al. Angiotensin II increases tissue endothelin and induces vascular hypertrophy. Reversal by ETA-receptor antagonist. Circulation 1997;96:1593–7.
O’Keefe JH, Wetzel M, Moe RR, Brosnahan K, Lavie CJ. Should an angiotensin-converting enzyme inhibitor be standard therapy for patients with atherosclerotic disease? J Am Coll Cardiol 2001;37:1–8.
Moser M, Setaro JF. Antihypertensive drug therapy and regression of left ventricular hypertrophy: a review with a focus on diuretics. Eur Heart J 1991;12:1034–9.
Masaki H, Kurihara T, Yamaki A, et al. Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest 1998;101:527–35.
Schmeider RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: a meta-analysis of randomized double-blind studies. JAMA 1996;275:1507–13.
Malmqvist K, Kahan T, Edner M, et al. Regression of left ventricular hypertrophy in human hypertension with irbesartan. J Hypertens 2001;19:1167–76.
Dahlof B, Devereux RB, Kjeldsen S, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002;359:995–1003.
Kohya T, Yokoshiki H, Tohse N, et al. Regression of left ventricular hypertrophy prevents ischemia-induced lethal arrhythmias. Beneficial effect of angiotensin II blockade. Circ Res 1995;76:892–9.
Kagoshima T, Masuda J, Sutani T. Angiotensin II receptor antagonist, TCV-116, prevents myocardial hypertrophy in spontaneously hypertensive rats. Blood Press 1994;5:89–93.
Bruckschlegel G, Holmer SR, Jandeleit K, et al. Blockade of the renin-angiotensin system in cardiac pressure-overload hypertrophy in rats. Hypertension 1995;25:250–9.
Verdecchia P, Schillaci G, Borgioni C, et al. Prognostic signifi- cance of serial changes in left ventricular mass in essential hypertension. Circulation 1998;97:48–54.
Warner JG, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567–722.
Soufer R, Wohlgelernter D, Vita NA, et al. Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardiol 1985;55:1032–6.
Setaro JF, Zaret BL, Schulman DS, Black HR, Soufer R. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981–6.
Perry GJ, Wei C, Hakes GH, et al. Angiotensin II receptor blockade does not improve left ventricular function and remodeling in subacute mitral regurgitation the dog. J Am Coll Cardiol 2002;39:1374–9.
Gaasch WH, Aurigemma GP. Inhibition of the renin-angiotensin system and the left ventricular adaptation to mitral regurgitation. J Am Coll Cardiol 2002;39:1380–3.
Pitt B, Zannad F, Remme WJ, et al. for The Randomized Aldactone Evaluation Study Investigators. The effects of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17.
Pfeffer MA, Braunwald E, Moye LA, & SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival And Ventricular Enlargement Trials. N Engl J Med 1992;327:669–77.
Garg R, Yusuf S, & Collaborative Group of ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450–6.
The SOLVD Investigators. Effects of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327:685–91.
Chaput AJ. Persistency with angiotensin receptor blockers (ARB) versus other antihypertensives (AHT) using the Saskatchewan database [abstract]. Can J Cardiol 2000;16(Suppl F):194F.
Tsutamoto T, Wada A, Maeda K, et al. Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6, and soluble adhesion molecules in patients with chronic heart failure. J Am Coll Cardiol 2000;35:714–211.
Crozier I, Ikram H, Awan N, et al. Losartan in heart failure. Hemodynamic effects and tolerability. Circulation 1995;91:691–77.
Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747–52.
Pitt B, Poole-Wilson PA, Segal R, et al. 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 2000;355:1582–7.
Cohn JN, Tognoni G, & Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure (Val-HeFT). N Engl J Med 2001;345:1667–75.
Swedberg K, Pfeffer M, Granger C, & CHARM Program Investigators. Candesartan in heart failure-assessment of reduction in mortality and morbidity (CHARM): rationale and design. J Card Fail 1999;5:276–82.
Higashi Y, Sasaki S, Nakagawa K, et al. A comparison of angiotensin converting enzyme inhibitors, calcium antagonists, beta-blockers, and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study. J Am Coll Cardiol 2000;35:284–91.
Prasad A, Tupas-Habib T, Schenke WH, et al. Acute and chronic angiotensin-1 receptor antagonism reverses endothelial dysfunction in atherosclerosis. Circulation 2000;101:2349–54.
Schiffrin EL, Deng LY, Larochelle P. Progressive improvement in the structure of resistance arteries of hypertensive patients after 2 years of treatment with an angiotensin-1 converting enzyme inhibitor. Comparison with effects of a β-blocker. Am J Hypertens 1995;8:229–36.
Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial function in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation 2000;101:1653–9.
Laflamme AK, Oster L, Cardinal R, de Champlain J. Effects of renin-angiotensin blockade on sympathetic reactivity and betaadrenergic pathway in the spontaneously hypertensive rat. Hypertension 1997;30(2 Pt 1):278–87.
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Perazella, M.A., Setaro, J.F. Renin-angiotensin-aldosterone system: Fundamental aspects and clinical implications in renal and cardiovascular disorders. J Nucl Cardiol 10, 184–196 (2003). https://doi.org/10.1067/mnc.2003.392
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DOI: https://doi.org/10.1067/mnc.2003.392