Abstract
Effective treatment of high blood pressure levels represents a crucial point in reducing global cardiovascular risk, and several studies have clearly demonstrated a significant reduction in cardiovascular and renal morbidity and mortality with a more intensive blood pressure-lowering treatment. Other factors beyond blood pressure control may be important in reducing the risk related to hypertension. Pharmacologic agents blocking the renin-angiotensin system, in particular the angiotensin II-receptor blocker (ARB), a novel class of antihypertensive agents, represent an important addition to the therapeutic options for hypertension management, and recent large, international, randomized, trials have demonstrated that ARBs have clinical benefits across the spectrum of disease severity. In this article, we provide some evidence derived from these trials, supporting a role for ARBs in primary and secondary prevention of cardiovascular and renal disease, beyond blood pressure control.
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References and Recommended Reading
Hansson L, Zanchetti A, Carruthers SG, et al.: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. The HOT Study Group. Lancet 1998, 351:1755–1762.
Blood Pressure Lowering Treatment Trialists’ Collaboration: Effect of angiotensin-converting enzyme inhibitors, calcium antagonists, and other blood pressure lowering drugs: results of prospectively designed overviews of randomized trials. Lancet 2000, 355:1955–1964.
MacMahon S, Peto R, Cutler J, et al.: Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990, 335:765–774.
Kannel WB, Ho K, Thom T: Changing epidemiological features of cardiac failure. Br Heart J 1994, 72(Suppl):S3-S9.
Andersson OK, Almgren T, Persson B, et al.: Survival in treated hypertension: follow up study after two decades. Br Med J 1998, 317:167–71.
Ruilope LM, Coca A, Volpe M, Waeber B: ACE inhibition and cardiovascular mortality and morbidity in essential hypertension: the end of the search or a need for further investigations? Am J Hypertens 2002, 15:367–371.
Dahlof B, Devereux RB, Kjeldsen SE, et al.: For The LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For End-point reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002, 359:995–1003. Provides evidence on the ability of the ARB losartan to prevent stroke in hypertensive patients with left ventricular hypertrophy beyond blood pressure control.
Lithell H, Hansson L, Skoog I, et al.: The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. The SCOPE Study Group. J Hypertens 2003, 21:875–886.
Kjeldsen SE, Dahlof B, Devereux RB, et al.: Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. LIFE (Losartan Intervention for Endpoint Reduction) Study Group. JAMA 2002, 288:1491–1498.
Devereux RB, Dahlof B, Gerdts E, et al.: Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension(LIFE) trial. Circulation 2004, 110:1456–1462.
Wachtell K, Olsen MH, Dahlof B, et al.: Microalbuminuria in hypertensive patients with electrocardiographic left ventricular hypertrophy: The LIFE Study. J Hypertension 2002, 20:405–412.
Lewis E, Hunsicker L, Clarke W, et al.: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes (IDNT). The Collaborative Study Group. N Engl J Med 2001, 345:851–860.
Parving HH, Lehnert H, Brochner-Mortensen J, et al.: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. Irbesartan in Patients with type 2 Diabetes and Microalbuminuria (IRMA2) Study Group. N Engl J Med 2001, 345:870–878.
Viberti G, Wheeldon NM: Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. The Microalbuminuria Reduction with Valsartan (MARVAL) Study Investigators. Circulation 2002, 106:672–678.
Lindholm LH, Ibsen H, Dahlöf B, et al.: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. The LIFE Study Group. Lancet 2002, 359:1004–1010.
Pfeffer MA, McMurray J, Velazquez EJ, et al.: Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators. N Engl J Med 2003, 349:1893–1906.
Teo K, Yusuf S, Sleight P, et al.: Rationale, design, and baseline characteristics of two large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in highrisk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/ TRANSCEND) trials. The ONTARGET/TRANSCEND Investigators. Am Heart J 2004, 148:52–61.
Dickstein K, Kjekshus J, the OPTIMAAL Steering Committee: Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002, 360:60–75.
Pfeffer MA, Swedberg K, Granger CB, et al., for the CHARM Investigators and Committees: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall Programme. Lancet 2003, 362:759–766.
Cohn JN, Tognoni G, the Valsartan Heart Failure Trial Investigators: A randomized trial of the angiotensin II receptor blocker valsartan in congestive heart failure. N Engl J Med 2001, 345:1667–1675.
Pitt B, Poole-Wilson PA, Segal R, et al.: Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: a randomized trial. The Losartan Heart Failure Survival Study ELITE II. Lancet 2000, 355:1582–1587.
Bloom BS: Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998, 20:671–681.
Weber MA, Bakris GL, Neutel JM, et al.: Quality of life measured in a practice-based hypertension trial of an angiotensin receptor blocker. J Clin Hypertens (Greenwich) 2003, 5:322–329.
Dzau VJ, Mukoyama M, Pratt RE: Molecular biology of angiotensin receptors: target for drug research? J Hypertens 1994, 12(Supp l2):S1-S5.
de Gasparo M, Catt KJ, Inagami T, et al.: International Union of Pharmacology. XXIII. The Angiotensin II receptors. Pharmacol Rev 2000, 52:415–472.
Berk BC, Vekshtein V, Gordon HM, Tsuda T: Angiotensin IIstimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension 1989, 13:305–314.
Geisterfer AA, Peach MJ, Owens GK: Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res 1988, 62:749–856.
Naftilan AJ, Pratt RE, Dzau VJ: Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth cells. J Clin Invest 1989, 83:1419–1424.
Stouffer GA, Owens GK: Angiotensin II-induced mitogenesis of spontaneously hypertensive rat-derived cultured smooth muscle cells is dependent on autocrine production of transforming growth factor. Circ Res 1992, 70:820–828.
Itoh H, Mukoyama M, Pratt RE, et al.: Multiple autocrine growth factors modulate vascular smooth muscle cells response to angiotensin II. J Clin Invest 1993, 91:2268–2274.
Taubman MB, Berk BC, Izumo S, et al.: Angiotensin II induces c-fos mRNA in aortic smooth muscle: role of Ca2+ mobilization and protein kinase C activation. J Biol Chem 1989, 264:526–530.
Naftilan AJ, Gilliland GK, Elderige CS, Kratt AS: Induction of the protooncogene c-jun by angiotensin II. Mol Cell Biol 1990, 10:5536–5540.
Ruiz-Ortega M, Lorenzo O, Ruperez M, et al.: Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension 2001, 38:1382–1387.
Raij L: Hypertension and cardiovascular risk factors: role of the angiotensin II-nitric oxide interaction. Hypertension 2001, 37:767–773.
Volpe M, Musumeci MB, De Paolis P, et al.: Angiotensin II AT2 receptor subtype: an uprising frontier in cardiovascular disease? J Hypertens 2003, 21:1429–1443. Provides a large review of the current knowledge on the angiotensin II-receptor network.
Griendling KK, Rittenhouse SE, Brock TA, et al.: Sustained diacylglycerol formation from inositol phospholipids in angiotensin II-stimulated vascular smooth muscle cells. J Biol Chem 1986, 261:5901–5906.
Saward L, Zahradka P: Angiotensin II activates phosphatidylinositol 3-kinase in vascular smooth muscle cells. Circ Res 1997, 81:249–257.
Berk BC, Corson MA: Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. Circ Res 1997, 80:607–616.
Marrero MB, Schieffer B, Paxton WG, et al.: Direct stimulation of JAK/STAT pathway by the angiotensin II AT1 receptor. Nature 1995, 375:247–250.
Atkinson AB, Robertson JI: Captopril in the treatment of clinical hypertension and cardiac failure. Lancet 1979, 2:836–839.
SOLVD Investigators: Effect of enalapril on survival in patients with angiotensin II AT2 receptor subtype reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991, 325:293–302.
Yusuf S, Sleight P, Pogue J, et al.: Effect 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 2000, 342:145–153.
Biollaz J, Durr J, Brunner HR, et al.: Escape from mineralcorticoid excess: the role of angiotensin II. J Clin Endocr Metab 1982, 54:1187–1193.
Crackower MA, Sarao R, Oudit GY, et al.: Angiotensin IIconverting enzyme is an essential regulator of heart function. Nature 2002, 417:822–828.
Timmermans PB, Wong PC, Chiu AT, et al.: Angiotensin II receptors and angiotensin II receptor antagonist. Pharmacol Rev 1993, 45:205–211.
de Gasparo M, Levens NR: Pharmacology of angiotensin II receptors in the kidney. Kidney Int 1994, 46:1486–1491.
Zhuo J, Alcorn D, Allen AM, Mendelsohn FA: High resolution localization of angiotensin II receptors in rat renal medulla. Kidney Int 1992, 42:1372–1380.
Zhuo J, Alcorn D, Harris PJ, Mendelsohn FAO: Localization and properties of angiotensin II receptors in rat kidney. Kidney Int 1993, 44(Suppl 42):S40-S46.
Navar LG, Inscho EW, Majid SA, et al.: Paracrine regulation of the renal microcirculation. Physiol Rev 1996, 76:425–536.
Gigante B, Rubattu S, Russo R, et al.: Opposite feedback control of renin and aldosterone biosynthesis in the adrenal cortex by angiotensin II AT1-subtype receptors. Hypertension 1997, 30:563–568.
Zhuo J, McGregor DP, Mendelsohn FAO: Comparative distribution of angiotensin II receptor subtypes in mammalian adrenal glands. In Adrenal Glands, Vascular System, and Hypertension. Edited by Vinson GP, Anderson DC. Melbourne: Journal of Endocrinology; 1996:53–68.
Zhuo J, Allen AM, Yamada H, et al.: Localization and properties of the angiotensin converting enzyme and angiotensin receptors in the heart. In The Cardiac Renin-Angiotensin System. Edited by Lindpaintner K, Ganten D. New York: Futura; 1994:63–68.
Kobayashi M, Furukawa Y, Chiba S: Positive chronotropic and inotropic effects of angiotensin II in the dog heart. Eur J Pharmacol 1978, 50:17–25.
Allen AM, McGregor DP, Chai SY, et al.: Angiotensin II receptor binding associated with nigrostriatal dopaminergic neurons in human basal ganglia. Ann Neurol 1992, 32:339–344.
World Health Organization: 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003, 21:1983–1992.
Chobanian A, Bakris G, Black H, et al.: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003, 289:2560–2571.
2003 European Society of Hypertension: European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertension 2003, 21:1011–1053.
Weber MA, Julius S, Kjeldsen SE, et al.: Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet 2004, 363:2049–2051.
Julius S, Kjeldsen SE, Weber M, et al., for the VALUE trial group: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004, 363:2022–2031.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. 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 2002, 288:2981–2997.
Niklason A, Hedner T, Niskanen L, Lanke J, for the Captopril Prevention Project (CAPPP) Study Group: Development of diabetes is retarded by ACE inhibition in hypertensive patients--a subanalysis of the Captopril Prevention Project (CAPPP). J Hypertens 2004, 22:645–652.
Verdecchia P, Reboldi G, Angeli F, et al.: Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 2004, 43:963–969.
Sharma AM, Janke J, Gorzelniak K, et al.: Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension 2002, 40:609–611.
Sowers JR: Insulin resistance and hypertension. Am J Physiol Heart Circ Physiol 2004, 286:H1597-H1602.
Brenner BM, Cooper ME, de Zeeuw D, et al.: Losartan reduces the costs associated with diabetic end-stage renal disease: the RENAAL study economic evaluation. Diabetes Care 2003, 26:683–687.
Barnett AH, Bain SC, Bouter P, et al., for the Diabetics Exposed to Telmisartan and Enalapril (DETAIL) Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004, 351:1952–1961.
Granger CB, McMurray JJ, Yusuf S, et al., for the CHARM Investigators and Committees: Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function intolerant to angiotensin-convertingenzyme inhibitors: the CHARM-Alternative trial. Lancet 2003, 362:772–776.
McMurray JJ, Ostergen J, Swedberg K, et al., for the CHARM Investigators and Committees: Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-Added trial. Lancet 2003, 362:767–771. Provides evidence on the additive beneficial effect of the ARB candesartan in patients with heart failure treated with ACEIs.
Yusuf S, Pfeffer MA, Swedberg K, et al., for the CHARM Investigators and Committees: CHARM-Preserved Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003, 362:777–781.
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Volpe, M., Tocci, G. & Pagannone, E. Angiotensin II-receptor antagonist in the treatment of hypertension. Current Science Inc 7, 287–293 (2005). https://doi.org/10.1007/s11906-005-0027-y
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DOI: https://doi.org/10.1007/s11906-005-0027-y