More than a century of research on the renin-angiotensin system (RAS) has uncovered the widespread involvement of angiotensin II (Ang II) in the pathophysiology of cardiovascular diseases. A number of outcomes-based mega trials utilising hard clinical endpoints have revealed beneficial effects of angiotensin receptor antagonists (AIIAs/ARBs) in patients with hypertension, heart failure, diabetic nephropathy, and post-myocardial infarction (MI). The results of these studies not only emphasise the importance of Ang II in the pathophysiology of these diseases but have provided the basis for an evidence-based approach for the use of AIIAs in clinical practice. It is hoped that the next 100 years of research into the RAS will uncover hitherto unimaginable therapeutic opportunities.
Silverstein RL, Fenves AZ, Ram CVARBs and target organ protection. Exploring benefits beyond their antihypertensive effects. Postgrad Med2004;116:31-8,41.
2.
Wagenaar LJ , Voors AA, Buikema H., van Gilst WHAngiotensin receptors in the cardiovascular system. Can J Cardiol2002;18:1331-9.
3.
Nicholls MG , Robertson JI, Inagami T.The renin-Angiotensin system in the twenty-first century. Blood Press2001;10:327-43.
4.
Schiffrin ELVascular and cardiac benefits of angiotensin receptor blockers. Am J Med2002;113:409-18.
5.
Ferrario CM , Chappell MCNovel angiotensin peptides. Cell Mol Life Sci2004;61:2720-7.
6.
Tallant EA, Ferrario CM, Gallagher PEAngiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol2005;289: H1560-H1566.
7.
Dahlof B., Devereux RB, Kjeldsen SE et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet2002;359:995-1003.
8.
Julius S., Kjeldsen SE, Weber M. et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet2004;363:2022-31.
9.
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. J Hypertens2003;21:875-86.
10.
Swedberg K. , Pfeffer M., Granger C. et al. Candesartan in heart failure--assessment of reduction in mortality and morbidity (CHARM): rationale and design. CHARM-Programme Investigators. J Card Fail1999;5:276-82.
11.
Granger CB, McMurray JJ, Yusuf S. et al. Effects of candesartan in patients with chronic heart failure an Reduced left-ventricular systolic function intolerant to angiotensinconverting-enzyme inhibitors: the CHARM-Alternative trial. Lancet2003;362:772-6./V^x"^
12.
McMurray JJ , Ostergren J., Swedberg K. et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensinconverting-enzyme inhibitors: the CHARM-Added trial . Lancet2003;362:767-71.
13.
Yusuf S., Pfeffer MA, Swedberg K. et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial . Lancet2003;362:777-81.
14.
Dickstein K. , Kjekshus J.Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet2002;360:752-60.
15.
Pfeffer MA, McMurray JJ, Velazquez EJ et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med2003;349:1893-906.
16.
Brenner BM, Cooper ME, de Zeeuw D. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med2001;345:861-9.
17.
Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the Angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med2001;345:851-60.
18.
Parving HH, Lehnert H., Brochner-Mortensen J., Gomis R., Andersen S., Arner P.The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med2001;345:870-8.
19.
Nicholls MG , Robertson JIThe renin-angiotensin system in the year 2000 . J Hum Hypertens2000;14:649-66.
20.
Roberston JIS.Epidemiology of the renin-angiotensin system in hypertension. In: Bulpitt CJ, ed. Epidemiology of HypertensionAmsterdam: Elsevier , 2000:389-427.
21.
Alderman MH , Ooi WL, Cohen H., Madhavan S., Sealey JE, Laragh JHPlasma renin activity: a risk factor for myocardial infarction in hypertensive patients. Am J Hypertens1997;10:1-8.
22.
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. Lancet2000;355:1582-7.
23.
Cohn JN, Tognoni G.A randomized trial of the Angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med2001;345:1667-75.
24.
Dahlof B., Burke TA, Krobot K., Carides GW, Edelman J., Devereux R.Population impact of losartan use on stroke in the European Union (EU): projections from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial. J Hum Hypertens2004;18:367-73.
25.
Wachtell K. , Hornestram B.,Lehto M. et al. Cardiovascular mortality and morbidity in hypertensive patients with atrial fibrillation: the LIFE trial E . J Am Coll Cardiol2005;45:705-11.
26.
Levy PJ, Yunis C., Owen J., Brosnihan KB, Smith R., Ferrario CMInhibition of platelet aggregability by losartan in essential hypertension . Am J Cardiol2000;86:1188-92.
27.
Ibsen H., Wachtell K., Olsen MH et al. Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy. J Hypertens2004;22:1805-11.
28.
Hoieggen A. , Alderman MH, Kjeldsen SE et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE trial. Kidney Int2004 ;65:1041-9.
29.
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 . Circulation2004;110:1456-62.
30.
Carlberg B. , Samuelsson O., Lindholm LHAtenolol in hypertension: is it a wise choice?Lancet2004;364:1684-9.
31.
Pepine CJ, Handberg EM, Cooper-DeHoff RM et al. A calcium antagonist vs. a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA2003;290:2805-16.
32.
Edelman JM, Lyle PA, ZhAng Z.Letter to the editor. Ann Intern Med2004;140:W-29.
33.
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) . Lancet1997;349:747-52.
34.
Lindholm LH , Ibsen H., Dahlof 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. Lancet2002;359:1004-10.
35.
Lindholm LH , Dahlof B., Edelman JM et al. Effect of losartan on sudden cardiac death in people with diabetes: data from the LIFE trial . Lancet2003;362:619-20.
36.
Lee VC, Rhew DC, Dylan M., Badamgarav E., Braunstein GD, Weingarten SRMeta-analysis: Angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med2004;141:693-704.
